JP6334066B2 - Substituted N- (pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as a Janus kinase inhibitor - Google Patents

Description

  The present invention relates to substituted N- (pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine and its use as a Janus kinase inhibitor.

  Janus kinase (JAK) occupies a part of the various action roles of tyrosine phosphorylase in cytoplasmic proteins. A series of diverse actions are performed through signal transducer and activator of transcription (STAT), but belong to an important part as a starting point of cell signal transduction initiated by cytokines.

  JAK is widely involved throughout the cytokine expression initiation mechanism. Four types of JAK proteins (JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)) and seven types of STAT molecules are known as initiation factors. More specifically, JAK proteins play an important role in the endogenous and adaptive immune system. Regarding the pathogenesis of rheumatoid arthritis, it was observed that cytokine receptors having a general γ chain are related to protein expression of JAK1 and JAK3. It was also confirmed that the expression of many cytokines and hormones is involved in intracellular signal transduction. This suggested the possibility that the expression of cytokines pathologically related to the pathogenic mechanism is reduced through JAK1 and JAK3 inhibition. Therefore, rheumatoid arthritis, systemic lupus erythematosus, minor articular rheumatoid arthritis, arthritis, asthma, chronic obstructive pulmonary disease (COPD), tissue fibrosis (eg, myelofibrosis), eosinophilic acid To treat inflammation, esophagitis, inflammatory bowel disease, transplant rejection, graft-versus-host disease, psoriasis, myositis, multiple sclerosis, inflammation, and autoimmune diseases caused by increased bulbs Compounds that inhibit JAK proteins, such as JAK1 and JAK3, may be useful.

  Rheumatoid arthritis is a progressive autoimmune disease with inflammation, tenderness and damage in the joints. Inflammatory cytokines (eg, tumor necrosis factor) are secreted by the activity of T lymphocytes and B lymphocytes, and JAK enzymes (JAK1 and JAK3) relay signal transcription and activity from inflammatory cytokines, Allows cytokine secretion and causes joint inflammation and damage. Of many cytokines, IL-1, IL-6, and IL-16 are also associated with the growth of cells that mediate the immune inflammatory response, but are also closely associated with the development of rheumatoid arthritis. Numerous studies conducted through humans and animals have also revealed that gene expression via the JAK-STAT pathway plays an important role in regulating inflammatory responses.

  The Vandeghinste (WO 2005/124342) research team revealed that JAK1 inhibition is a target mechanism useful for the treatment of various diseases including osteoarthritis. Since JAK1 plays an essential role in lymphocyte development and maturation, it was observed in a JAK1 knockout mouse that it died within 24 hours after birth due to lymphocyte immaturity. In JAK1-negative cells, the γc chain did not operate due to the inactivation of the type 2 cytokine receptor, and the related cytokine receptor, that is, the receptor utilizing the gp130 molecule did not operate.

  Of the JAK proteins, in particular, JAK2 is associated with myeloproliferative diseases. That is, inhibiting JAK2 may be useful in the treatment of myeloproliferative diseases. In addition, all three proteins of JAK1, 2, and 3 are related to cancer. Among them, myelogenous leukemia (eg, acute myelogenous leukemia) (AML), lymphoblast It has also been confirmed to be useful in the treatment of tumors such as lymphoblastic leukemia (eg, acute lymphoblastic leukemia).

  In rheumatoid arthritis, if STAT1, STAT3, STAT4, and STAT6 expression transition in the JAK-STAT pathway is decreased, the inflammatory joint inflammation state will be improved, and an inflammatory cytokine (eg, TNF-α) that increases symptom expression It was confirmed that the control of the JAK-STAT pathway involved in the production of IL-1 and IL-6) is ideal for suppressing the progression of the disease state. In suppressing rheumatoid arthritis, acting on various mechanisms is effective in suppressing pathophysiological symptoms.

  Currently, no perfect treatment for rheumatoid arthritis has been developed, and research on related mechanisms is ongoing. Many other factors related to immune and inflammatory diseases act on the pathogenesis of rheumatoid arthritis. For these reasons, when developing drugs to be applied to rheumatoid arthritis, other immune and inflammatory diseases (eg, proliferative diseases, transplant rejection, cartilage hyperplasia and cartilage dysplasia, IL-6 And interferon hypersecretion-related diseases). Therefore, through the present invention, a drug that can be produced can be developed by synthesizing, producing, and formulating a substance that can be used for the diseases and symptoms described above.

  The uniform phase provides a compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof.

  Another aspect provides a pharmaceutical composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

  Another aspect provides a method of modulating the activity of JAK utilizing a compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer.

  Another aspect provides a method of administering a compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, to a subject to treat a disease in the individual.

  Another aspect provides a method for preparing the compound of Formula 1.

The uniform phase provides a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or stereoisomer thereof:
1

In Formula 1, R ¹ is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl,
R ² and R ³ together _form- (C _2-6 alkyl)-or-(C _2-6 alkenyl)-
R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ —, —S (═O) — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is H; halo; CN; NO ₂ ; N ₃ ; C _1-10 alkyl: C _2-10 alkenyl; C _2-10 alkynyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 C _5-20 aryl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl); C _3-7 cyclo Alkyl; heterocycloalkyl having 3 to 7 ring atoms, optionally substituted with —C (C═O) (C _1-6 alkyl); heteroaryl having 3 to 7 ring atoms Heteroaryl- (C _1-10 alkyl) having 3 to 7 ring atoms;-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ;-( C _{1- 10} alkyl) -O- _{(C 1-6} A _{Kill); (C 1-10} ^{alkyl) -C (= O) NR a} R b; or _{- (C 1-10} ^{alkyl) -NR a C (= O)} R b or _{- (C 1-10} alkyl) - NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently of each other H or C _1-6 alkyl.

  A compound of formula 1 in a uniform phase, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof is used as an inhibitor of JAK.

  A pharmaceutical composition comprising a compound of Formula 1 according to another aspect, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, is used in the treatment of JAK-related diseases.

  According to the method for modulating the activity of JAK using the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer thereof according to another aspect, the activity of JAK is efficiently regulated. be able to.

  According to another aspect of the method of treating a disease in an individual, the compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, can treat the disease in the individual efficiently. it can.

  According to the method for producing the compound of Formula 1 according to another aspect, the compound of Formula 1 can be produced efficiently.

It is the figure which showed the hind paw edema volume of the arthritis model mouse by the drug administration time after primary immunization.

The uniform phase provides a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or stereoisomer thereof:
1

In Formula 1, R ¹ is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl,
R ² and R ³ together _form- (C _2-6 alkyl)-or-(C _2-6 alkenyl)-
R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ —, —S (═O) — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is H; halo; CN; NO ₂ ; N ₃ ; C _1-10 alkyl: C _2-10 alkenyl; C _2-10 alkynyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 C _5-20 aryl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl); C _3-7 cyclo Alkyl; heterocycloalkyl having 3 to 7 ring atoms, optionally substituted with —C (C═O) (C _1-6 alkyl); heteroaryl having 3 to 7 ring atoms Heteroaryl- (C _1-10 alkyl) having 3 to 7 ring atoms;-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ;-( C _{1- 10} alkyl) -O- _{(C 1-6} A _{Kill); (C 1-10} ^{alkyl) -C (= O) NR a} R b; or _{- (C 1-10} ^{alkyl) -NR a C (= O)} R b or _{- (C 1-10} alkyl) - NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently of each other H or C _1-6 alkyl.

In the present invention, in Formula 1, R ¹ is also linear or branched C _1-6 alkyl, for example, linear or branched C _1-3 alkyl. The C _1-6 alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter-butyl, pentyl, neopentyl or hexyl. In Formula 1, R ¹ is also a linear or branched C _2-6 alkenyl, such as C _2-3 alkenyl. In Formula 1, R ¹ is also a linear or branched C _2-6 alkynyl, for example C _2-3 alkynyl.

In the present invention, R ² and R ³ together _form- (C _2-6 linear or branched alkyl)-. R ² and R ³ together form, for example, — (CH ₂ ) _n — where n is 2 to 6. R ² and R ³ together _form- (C _2-6 linear or branched alkenyl)-.

In the present invention, W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, It is also -C (= S) NR < ⁵ >-or -S (= O) _2- .

In the present invention, R ⁶ represents C _1-10 alkyl (eg, C _1-6 alkyl); C _2-10 alkenyl (eg, C _2-6 alkenyl); C _2-10 alkynyl (eg, C _2-6) Alkynyl); C _1-6 haloalkyl (eg: C _1-3 haloalkyl); C _1-10 alkyl (eg: C _1-6 alkyl), C _1-6 haloalkyl (eg: C _1-3 haloalkyl), halo, C, optionally substituted with one or more substituents selected from the group consisting of CN, NO ₂ and —O— (C _1-10 alkyl) (eg, —O— (C _1-6 alkyl)) 3 to 7 rings, optionally substituted with _5-20 aryl (eg C _6-12 aryl); C _3-7 cycloalkyl; —C (C═O) (C _1-6 alkyl) Heterocycloalkyl having atoms (eg piperidinyl); 3 To heteroaryl having 7 ring atoms (e.g. furanyl, pyridinyl or imidazolyl); three to heteroaryl having 7 ring atoms (e.g. furanyl, pyridinyl or imidazolyl) - (C _1-10 alkyl); -(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ;-( C _1-10 alkyl) -O- (C _1-6 alkyl); (C _1-10 alkyl)- C (═O) NR ^a R ^b ; or — (C _1-10 alkyl) —NR ^a C (═O) R ^b or — (C _1-10 alkyl) —NR ^c R ^d , where R ^a , R ^b , R ^c and R ^d , independently of one another, are H or C _1-6 alkyl. R ⁶ is, for example, C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-3 haloalkyl (eg C _1-3 trifluoroalkyl); C _1-6 alkyl, C _1- Optionally substituted with one or more substituents selected from the group consisting of ₃ haloalkyl (eg C _1-3 trifluoroalkyl), halo, CN, NO ₂ and —O— (C _1-6 alkyl) , C _6-12 aryl (eg phenyl, naphthalenyl or biphenyl); C _3-7 cycloalkyl (eg cyclopropyl or cyclohexyl); selectively substituted with —C (C═O) (C _1-6 alkyl) Heterocycloalkyl having 3 to 7 ring atoms (eg piperidinyl); heteroaryl having 3 to 7 ring atoms (eg furanyl, pyridinyl or imi) Zoriru); three to heteroaryl having 7 ring atoms - _{(C 1-6} alkyl) (e.g. furanyl - _{(C 1-6} alkyl), pyridinyl - _{(C 1-6} alkyl) or imidazolyl - (C _1-6 alkyl));-(C _1-6 alkyl) -CN;-(C _1-6 alkyl) -N ₃ ;-(C _1-6 alkyl) -O- (C _1-3 alkyl); C _1-6 alkyl) —C (═O) NR ^a R ^b ; or — (C _1-6 alkyl) —NR ^a C (═O) R ^b or — (C _1-6 alkyl) —NR ^c R ^d Where R ^a , R ^b , R ^c and R ^d are independently of each other H or C _1-3 alkyl.

One specific example of the compound of Formula 1 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer is:
In Formula 1, R ¹ is C _1-6 alkyl,
R ² and R ³ together _form- (C _2-6 alkyl)-
R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is selected from the group consisting of C _1-10 alkyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl). C _5-20 aryl; C _3-7 cycloalkyl; —C (C═O) (C _1-6 alkyl), optionally substituted with one or more substituents selected from Heterocycloalkyl having 3 to 7 ring atoms; Heteroaryl having 3 to 7 ring atoms; Heteroaryl- (C _1-10 alkyl) having 3 to 7 ring atoms; C _1-10 alkyl) -CN _{;-( C 1-10 alkyl)} -N _{3 ;-( C 1-10} alkyl) -O- _{(C 1-6 alkyl); (C 1-10} alkyl) -C ( _{^{= O) NR a R b ;-(}} C 1-10 Al ^{Le) -NR a C (= O)} R b; or _{- (C 1-10} alkyl) ^-NR c ^{R d, wherein, R a, R b, R} c and ^{R d} are independently of each other , H or C _1-6 alkyl.

Another specific example of the compound of the formula 1 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer is
In Formula 1, R ¹ is methyl,
R ² and R ³ together form —CH ₂ CH ₂ —
R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is selected from the group consisting of C _1-10 alkyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl). C _5-20 aryl; C _3-7 cycloalkyl; —C (C═O) (C _1-6 alkyl), optionally substituted with one or more substituents selected from Heterocycloalkyl having 3 to 7 ring atoms; heteroaryl having 3 to 7 ring atoms; heteroaryl-C _1-10 alkyl having 3 to 7 ring atoms; — (C _{1 -10} alkyl) -CN;-(C _1-10 alkyl) -N ₃ ;-(C _1-10 alkyl) -O- (C _1-6 alkyl); (C _1-10 alkyl) -C (= O ) ^NR a ^R b _{;-( C 1-10} alkyl A ^{-NR a C (= O) R} b ;-( C 1-10 alkyl) ^-NR c ^{R d, wherein, R a, R b, R} c and ^{R d} are independently of each other, H or C _1-6 alkyl.

Another specific example of the compound of formula 1 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer is:
In Formula 1, R ¹ is methyl,
R ² and R ³ together form —CH ₂ CH ₂ —
R ⁴ is —W ¹ —R ⁶ ,
W1 is either there is no such atom, or -C (= O) -, - C (= S) -, - C (= O) O -, - C (= O) NR 5 -, - C (= S ) NR ⁵ -or -S (= O) _2-
R ⁵ is H or C _1-6 alkyl;
R ⁶ is C _1-10 alkyl; trifluoro- (C _1-3 alkyl); C _1-10 alkyl, trifluoro- (C _1-3 alkyl), halo, CN, NO ₂ and —O— (C Phenyl, naphthalenyl or biphenyl; C _3-7 cycloalkyl; —C (C═O) (C _1-6 ), optionally substituted with one or more substituents selected from the group consisting of _1-10 alkyl) Piperidinyl or morpholinyl optionally substituted with alkyl); furanyl; pyridinyl; imidazolyl- (C _1-10 alkyl);-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ -(C _1-10 alkyl) -O- (C _1-6 alkyl); (C _1-10 alkyl) -C (= O) NR ^a R ^b ;-(C _1-10 alkyl) -NR ^a C (= O) R ^b _Or- (C _1-10 alkyl) -NR ^c R ^d , wherein Ra, R ^b , R ^c and R ^d are independently of each other H or C _1-6 alkyl.

Another specific example of the compound of Formula 1 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer has the general formula of Formula 2,
2

In Formula 2, R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is
When W ¹ does not have the atom, it is C _1-10 alkyl;
When W ¹ is —C (═O) —, C _1-10 alkyl; C _3-7 cycloalkyl;-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ; R ^a and R ^b are independently of each other —H or C _1-6 alkyl — (C _1-10 alkyl) —NR ^a C (═O) R ^b ; R ^a and R ^b are independently of each other; — (C _1-10 alkyl) —C (═O) NR ^a R ^b, which is H or C _1-6 alkyl; phenyl; substituted with one or more substituents selected from the group consisting of —CF ₃ and CN Piperidinyl substituted with —C (C═O) (C _1-6 alkyl); furanyl; pyridinyl; imidazolyl- (C _1-10 alkyl); — (C _1-10 alkyl) -O— (C _1-6 alkyl); or ^{R c} and ^{R d} are independently from each other Is H or _{C 1-6} alkyl _- a _{(C 1-10} alkyl) ^-NR c ^{R d,}
When W ¹ is —C (═S) —, it is — (C _1-10 alkyl) -CN;
When W ¹ is —C (═O) O—, it is — (C _1-10 alkyl);
When W ¹ is —C (═O) NR ⁵ , one or more selected from the group consisting of — (C _1-10 alkyl); C _3-7 cycloalkyl; phenyl; halo and C _1-10 alkyl Phenyl substituted with a substituent; biphenyl; or biphenyl substituted with one or more substituents selected from the group consisting of halo and C _1-10 alkyl;
When W ¹ is —C (═S) NR ^5, it is phenyl substituted with one or more —CF ₃ ;
When W ¹ is —S (═O) ₂ —, — (C _1-10 alkyl); —CF ₃ ; piperidinyl; morpholinyl; R ^c and R ^d are independently of each other, H or C _1-6 alkyl -(C _1-10 alkyl) -NR ^c R ^d ; phenyl;-(C _1-10 alkyl), -O- (C _1-6 alkyl), -CF ₃ , NO ₂ , CN and halo. Phenyl substituted with one or more selected substituents; naphthalenyl; — (C _1-10 alkyl), —O— (C _1-6 alkyl), — (C _1-6 haloalkyl), NO ₂ , Naphthalenyl substituted with one or more substituents independently selected from CN and halo.

The compound of Formula 1 of the present invention is also substituted with a detectable label. The detectable label can also be an optical label, an electrical label, a magnetic label or an indirect label. The optical label is a substance that generates a detectable optical signal, and is also a coloring substance such as a radioactive substance or a fluorescent substance. The indirect label indicates an enzyme capable of generating a detectable label as a result of binding to a specific substance such as an enzyme that converts a substrate with a chromogenic substance, or its substrate, antibody, or antigen. The optical label is also an isotope of an element constituting the compound of Chemical Formula 1. Therefore, the compound of the chemical formula 1 is one in which one or more of the elements constituting the compound are substituted with its isotopes, for example, radioactive isotopes. Examples of the isotope, 2H (may be represented by D, which means ^deuterium), (can be represented by T, which means ^{tritium) 3 H, 11 C, 13} C, 14 C, 13 N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I and the like. The compound of formula 1 of the present invention substituted with a detectable label is used to confirm the position of Janus kinase (JAK) in a cell or an individual. Thereby, it is used to identify and treat a disease site associated with increased JAK activity.

  The compounds of the present invention are also in the form of their pharmaceutically acceptable salts. Said salts are the usual acid addition salts used in the field of JAK inhibitors, for example salts derived from inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, and acetic acid, propionic acid , Succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid Salts derived from organic acids such as oxalic acid or trifluoroacetic acid. The salts also include conventional metal salt forms such as salts derived from metals such as lithium, sodium, potassium, magnesium or calcium. The acid addition salt or metal salt is produced by a usual method.

  The compounds of the present invention are also in the form of their solvates. “Solvate” means a complex or aggregate formed by one or more solute molecules, ie, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more solvent molecules. The solvate is also a complex or aggregate formed with, for example, water, methanol, ethanol, isopropanol or acetic acid.

The compounds of the invention are also in the form of their stereoisomers. The stereoisomers include all stereoisomers such as optical isomers (enantiomers) and partial stereoisomers (diastereomer). The compound may also be a stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. The separation of the specific stereoisomer is performed by one of ordinary methods known in the art. Some examples of the compounds of the present invention are those in which the specific stereoisomer has a greater JAK-inhibiting effect than the racemic mixture, for example, 3 to 40 times greater. In that case, the dosage can be reduced by using a specific stereoisomer. For example, the compound of Example 5 having an R configuration (IC ₅₀ value = 8.5 nM) is about 3.5 times higher than the racemic mixture of Example 55 (IC ₅₀ value = 29.3 nM). Has JAK1 inhibitory activity. Therefore, by separating a specific stereoisomer having a large inhibitory effect on JAK, for example, an optical isomer or a partial structural isomer, a disease associated with JAK can be efficiently treated.

  Unless otherwise indicated in connection with the compounds, compositions and methods of the present invention, the following terms have the following meanings.

The term “alkyl” means a linear or branched monovalent saturated hydrocarbon group. Unless otherwise defined, the alkyl group generally contains 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl and t-butyl), pentyl (eg n-pentyl, isopentyl and neopentyl), Including n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term “alkenyl” refers to a monovalent unsaturated hydrocarbon group having one or more straight or branched carbon-carbon double bonds. Unless otherwise defined, the alkenyl group typically contains 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The alkenyl group includes, for example, ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, cyclohexenyl, n-hex-3-enyl and the like.

  The term “alkynyl” refers to a monovalent unsaturated hydrocarbon group having one or more straight-chain or branched carbon-carbon triple bonds. Unless otherwise defined, the alkynyl group typically contains 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The alkynyl group includes, for example, ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

The term “haloalkyl” refers to an alkyl group having one or more halogen substituents. The haloalkyl group includes —CF ₃ , —C ₂ F ₅ , —CHF ₂ , —CCl ₃ , —CHCl ₂ and —C ₂ Cl ₅ . Unless otherwise defined, the haloalkyl group typically contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

  The term “aryl” means an aromatic hydrocarbon group having a single ring or multiple rings. The polycycle may include those having a fused ring (eg, naphthalene) and / or those having an unfused ring (eg, biphenyl). The polycycle also has, for example, 2, 3 or 4 rings. Unless otherwise defined, the aryl group generally has from 5 to 20, 6 to 15, 6 to 12, or 6 to 10 carbon ring atoms. Examples of the aryl group include phenyl, naphthalenyl (eg, naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, phenanthrenyl, and the like.

  The term “cycloalkyl” refers to a non-aromatice carbocycle comprising cyclized alkyl, alkenyl and alkynyl groups. The cycloalkyl group may include a single ring or multiple rings. The polycycle is, for example, one having 2, 3 or 4 fused rings. Unless otherwise defined, the cycloalkyl group typically contains 3 to 10, or 3 to 7 ring carbon atoms. Such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcarnyl, adamantyl and the like.

  The term “heterocycloalkyl” means a non-aromatic heterocycle containing one or more atoms selected from N, O or S and containing heteroatoms that form a ring. The heterocycloalkyl group includes a monocyclic structure or a polycyclic structure, for example, a structure having 2, 3 or 4 fused rings. Examples of “heterocycloalkyl” groups are morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxein, piperidinyl, pyrrolidinyl , Isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl and the like. Unless otherwise defined, the heterocycloalkyl group contains 3 to 10, 3 to 7, 5 to 7, or 5 to 6 atoms forming a ring.

  The term “heteroaryl” means a monovalent aromatic group having one or more heteroatoms selected from N, O and S as ring members. The heteroaryl group includes a monocyclic structure or a polycyclic structure. The polycycle also has, for example, 2, 3 or 4 fused rings. Unless otherwise defined, the heteroaryl group typically contains 3 to 10, 3 to 7, or 3 to 5 ring atoms. The heteroaryl group may also contain 1, 2 or 3 heteroatoms. Heteroaryl groups include, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, furanyl, thiazolyl, indolyl, Examples include pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiade-azolyl, isothiazolyl, benzothienyl, purinyl, benzimidazolyl, indolinyl and the like.

  The term “halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

  The term “arylalkyl” refers to an alkyl group substituted by an aryl group. “Aryl” and “alkyl” are as defined above.

  The term “heteroarylalkyl” refers to an alkyl group substituted by a heteroaryl group. “Heteroaryl” and “alkyl” are as defined above.

  Another aspect of the present invention is a therapeutically effective amount of a compound of formula 1 as defined above, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable Pharmaceutical compositions comprising such carriers are provided.

  The pharmaceutical composition is also for treating a disease associated with JAK. The disease may also be an autoimmune disease, immune dysfunction, viral disease, allergic disease, skin disease, disease associated with the IL-6 pathway, immune response, hyperproliferative disorder or cancer. The autoimmune disease is skin disease, multiple sclerosis, rheumatoid arthritis, pediatric arthritis, type I diabetes, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, Crohn's disease or autoimmune thyroid disease, The immune dysfunction is allograft rejection, graft-versus-host disease, and the viral diseases are Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, chickenpox, shingles A viral (VZV) or human papillomavirus (HPV) disease, wherein the cancer is prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, glioblastoma, leukemia, lymphoma or It is also multiple myeloma. The immune reaction is diarrhea, skin irritation, skin rash, contact dermatitis or allergic contact hypersensitivity reaction, and the allergic disease is also asthma, food allergy, atopic dermatitis or rhinitis. Diseases associated with the IL-6 pathway include Castleman's disease and Kaposi's sarcoma.

  In the composition, “therapeutically effective amount” means an amount sufficient to exhibit a therapeutic effect when administered to an individual in need of treatment. The term “treatment” means treating a disease or medical condition, eg, a JAK-related disease, in an individual, eg, a mammal, including a human, which includes: (a) of the disease or medical condition Developmental prevention, ie, prophylactic treatment of the patient; (b) Alleviation of the disease or medical condition, ie, causing removal or recovery of the disease or medical condition in the patient; (c) Suppression of the disease or medical condition I.e. slowing or stopping the progression of the disease or medical condition in the individual; or (d) reducing the disease or medical condition in the individual. The “effective amount” can be appropriately selected by those skilled in the art. The “effective amount” is 0.01 mg to 10,000 mg, 0.1 mg to 1,000 mg, 1 mg to 100 mg, 0.01 mg to 1,000 mg, 0.01 mg to 100 mg, 0.01 mg to 10 mg, or 0.0. Also from 01 mg to 1 mg.

  In the composition, the compound, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof is as described above.

  In the composition, “pharmaceutically acceptable carrier” refers to a substance, generally an inert substance, used in combination with an active ingredient to assist in the application of the active ingredient. The carrier includes common pharmaceutically acceptable excipients, additives or diluents. The carrier includes, for example, a filler, a binder, a disintergrant, a buffer, a preservative, an antioxidant, a lubricant, a flavoring agent, a thickener, a color former ( a coloring agent), an emulsifier, a suspending agent, a stabilizer and an isotonic agent.

  The compositions of the present invention may be administered orally or parenterally including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Accordingly, the compositions of the present invention are formulated into various forms such as tablets, capsules, aqueous solutions or suspensions. For oral tablets, excipients such as lactose, corn starch and lubricants such as magnesium stearate are usually added. In the case of capsules for oral administration, lactose and / or dried corn starch are used as diluents. When an oral aqueous suspension is required, the active ingredient can be combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredients are usually prepared and must be buffered by adjusting the pH of the solution to be suitable. For intravenous administration, the total concentration of solutes must be adjusted to impart isotonicity to the formulation. The composition according to the invention is also in the form of an aqueous solution comprising a pharmaceutically acceptable carrier, such as saline having a pH of 7.4. The solution is introduced into the patient's intramuscular bloodstream by local bolus injection.

  The compound of Formula 1 defined in the present invention can exhibit an effect of suppressing one or more JAK activities. Here, “inhibition” includes those that reduce the activity of one or more phosphorylases.

  “JAK” used in the present invention includes all Janus kinase enzymes. Some specific compounds of the invention inhibit the activity of JAK1, JAK2, JAK3 and TYK2. The compounds of some specific examples of the present invention selectively inhibit the activities of JAK1, JAK2 and TYK2. On the other hand, some other specific compounds selectively inhibit JAK1 alone. For example, the compound of Example 44 suppresses the activities of JAK1, JAK2, JAK3 and TYK2. Specifically, the compound of Example 44 inhibits the activities of JAK1, JAK2, JAK3 and TYK2 by 100%, 96%, 96% and 98% in the presence of 1 μM, respectively. Moreover, the compound of Example 39 selectively suppresses the activities of JAK1, JAK2, and TYK2. Specifically, the compound of Example 39 suppresses JAK1, JAK2, and TYK2 activities by 99%, 95%, and 93%, respectively, while JAK3 suppresses only 65% in the presence of 1 μM. Moreover, the compound of Example 60 selectively suppresses the activity of JAK1. Specifically, the compound of Example 60 inhibits the activity of JAK2, JAK3, and TYK2 in the presence of 1 μM by −3%, −14%, and 0%, respectively, while JAK1 inhibits 96%. . Here, the inhibitory effect is a measure of the degree to which JAK suppresses the conversion of ADP to ATP in the presence of the compound, and the measured absorbance value is measured lower than the standard absorbance curve. The inhibitory effect has a negative value, which is measured below the negative control value and is substantially the same as 0% which does not show any inhibitory effect.

  The compounds described in the present invention are also selective for a particular JAK type. As used herein, the term “optionally” refers to the case where a compound exhibits a higher regulatory activity for a particular JAK than at least one or more JAKs. Some specific examples are inhibitors that are selective for JAK1 or JAK2 over JAK3 or TYK2. Other embodiments are inhibitors that are selective for JAK1 over JAK2, JAK3 and / or TYK2. In particular, since a JAK3 inhibitor can exhibit an immunosuppressive effect, an inhibitor selective for JAK2 compared to JAK3 is effective in treating cancers such as multiple myeloma and myelofibrosis without immunosuppressive side effects. Used for. The selectivity is also at least 5 times, 10 times, 20 times, 40 times, 100 times, 200 times, 500 times and 1,000 times. When compared with inhibitory ability (%) at 1 μM, some of the compounds of specific examples also have 44-fold selectivity for JAK1 over JAK2 (−91 <JAK1 (%) / JAK2 ( %) <44). In addition, some of the compounds of specific examples also have a 40-fold selectivity for JAK1 over JAK3 (−65 <JAK1 (%) / JAK3 (%) <40). In addition, some of the compounds of specific examples also have 62-fold selectivity in JAK1 over TYK2 (−19.75 <JAK1 (%) / TYK2 (%) <62). The selectivity can be measured by techniques known in the art as routine methods. In some embodiments, the selectivity is tested at the Km of each enzyme.

  The pharmaceutical composition of the present invention is combined with one or more other therapeutic agents for treating diseases associated with JAK. Other therapeutic agents include chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents and anticancer agents. In particular, the combination with a therapeutic agent for multiple myeloma can further increase the therapeutic response than a single formulation of JAK inhibitor without further toxicity issues. In the treatment for multiple myeloma, examples of drugs for combination treatment include melphalan, a combination drug of melphalan and prednisone, doxorubicin, dexamethasone, velcade and the like. The combination treatment generates a synergistic effect. Furthermore, the formulation of the compounds of the present invention can solve the drug resistance problem as shown by dexamethasone in the treatment of multiple myeloma. The agents for the combination therapy can be used in combination with the JAK inhibitor in a single dose or continuous administration form, or can be administered simultaneously or sequentially in separate dosage forms.

  Another aspect of the present invention is the use of a compound of formula 1 as defined above, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, in treating a disease associated with JAK. provide.

  Another aspect of the present invention is to provide a compound of formula 1 as defined above, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer in the manufacture of a medicament for treating a disease associated with JAK. Provide the use of.

  Another aspect of the present invention is the step of bringing JAK into contact with a compound of Formula 1 as defined above, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer thereof, to suppress the activity of JAK. A method of suppressing the activity of JAK is provided.

  In the method, the contacting is performed in bitro or in vivo. In the method, the JAK is also present in a cell. Said JAK is also JAK1, JAK2, JAK3 or TYK2.

  Said suppression also reduces JAK activity. The suppression also reduces the activity of the specific JAK type to a higher level than other JAK types. For example, the suppression also selectively inhibits JAK1 in the presence of one or more of JAK1, JAK2, JAK3, and TYK2.

  Another aspect of the present invention provides a method for treating a disease in an individual comprising administering to the individual a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof. Provide a method of treating.

  In the above method, those skilled in the art can appropriately select the administration route at the time of administration depending on the patient's condition. Said administration may also be oral, parenteral or topical.

  In the above method, the dosage varies according to various factors such as the condition of the patient, the administration route, and the judgment of the attending physician as described above. Effective doses can be extrapolated from dose-response curves derived from in vitro experiments or animal model studies. The proportion and concentration of the compound of the invention present in the composition to be administered is determined by chemical properties, route of administration, therapeutic dosage and the like. The dose is administered to an individual in an effective amount of about 1 μg / kg to about 1 g / kg per day, or about 0.1 mg / kg to about 500 mg / kg per day. The dose will vary depending on the age, weight, sensitivity or symptoms of the individual.

  In the method, the disease is also a disease associated with JAK. The disease may also be an autoimmune disease, immune dysfunction, viral disease, allergic disease, skin disease, disease associated with the IL-6 pathway, immune response, hyperproliferative disorder or cancer. These are as described above. In addition, a therapeutically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof of the present invention is one or more for treating a disease associated with JAK. It is administered in combination with other therapeutic agents. Other therapeutic agents are as described above.

The compound of Formula 1 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer is produced by the production method according to the following Reaction Scheme 1.
Anti 1


In Reaction Formula 1, in Chemical Formulas 3, 4, 5, 6, 7, and 8, L ¹ and L ² each represent a leaving group, Pr ¹ and Pr ^{2 each} represent an amino protecting group, and X represents F, Cl, Br or I is shown, and R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1.

The method includes (a) reacting a compound of Formula 3 or a salt thereof with a compound of R ¹ -X ¹ to form a compound of Formula 4, a compound of Formula 4, and 6-halo-7- Reacting with deazapurine to produce a compound of formula 6; (b) reacting a compound of formula 3 or a salt thereof with 6-halo-7-deazapurine to produce a compound of formula 5; Reacting a compound of formula 5 with a compound of R ¹ -X ¹ to form a compound of formula 6; and (c) deprotecting the nitrogen of the pyrrolidine ring of the compound of formula 6 to obtain a compound of formula 7 (D) reacting the compound of Formula 7 with R ⁴ —X ² to form a compound of Formula 8; and (e) deprotecting the compound of Formula 8 to form a compound of Formula 1. Manufacturing the stage, and It provides a method for producing a compound of free Formula 1.

In the above method, in the step (a), “a compound of Formula 3 or a salt thereof is reacted with a compound of R ¹ -X ¹ to produce a compound of Formula 4”, and “a compound of Formula 5 and R ^“ Reacting with a compound of ^1- X ¹ to form a compound of formula 6” includes alkylation (eg, methylation), alkenylation or alkynylation.

  In the above method, “a step of reacting a compound of formula 4 with 6-halo-7-deazapurine to form a compound of formula 6” in step (a), and “a compound of formula 3 or a salt thereof, The “reaction with halo-7-deazapurine to form the compound of formula 5” is carried out with heating in a suitable solvent or under reflux conditions. The 6-halo-7-deazapurine can be purchased commercially. Said halo is for example also chloro.

  In said method, (c) “deprotecting nitrogen of pyrrolidine ring of compound of formula 6 to form compound of formula 7”, and (e) “deprotecting compound of formula 8 “The step of producing one compound” is performed by any known deprotection method.

In the above method, (d) “the step of reacting the compound of Chemical Formula 7 with R ⁴ —X ² to form the compound of Chemical Formula 8” is performed by substituting X ² with N.

  In the method, the term “leaving group” means a functional group or atom that is replaced by another functional group or atom in a substitution reaction, eg, a nucleophilic substitution reaction. For example, representative leaving groups include chloro, bromo and iodo groups; sulfonate groups such as dosylate, brosylate and nosylate; and alkyloxy groups such as acetoxy and trifluoroacetoxy.

  The term “protected” means that one or more functional groups of the compound are protected from undesired reactions utilizing a protecting or blocking group. Protected functional groups include, for example, carbamates (eg, tert-butoxycarbonyl) which are representative protecting groups for amino groups.

  The term “amino-protecting group” means a protecting group suitable for preventing undesired reactions at an amino group. Exemplary amino protecting groups are tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS) and tert-butyldimethyl. Including silyl (TBS).

One aspect of the present invention provides a method for preparing a compound of formula 1 comprising reacting a compound of formula 9 or a salt thereof with a compound of R4-L2 to produce a compound of formula 2:
Anti-2

In Reaction Scheme 2, R ⁷ is H or an amino protecting group, L ² is a leaving group, and R ⁴ is as defined for Chemical Formula 1.

  The compound of formula 9 is prepared by methods known in the art. For example, the compound of Formula 9 is prepared by first (R) -5-benzyl-N-methyl-5-azaspiro [2.4] heptane-7-amine and 6-halo-7-deazapurine in the presence of potassium carbonate. And (R) -N- (5-benzyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3- d] Prepared by obtaining pyrimidine-4-amine, which is reacted with hydrogen under a palladium / carbon catalyst. When R7 is an amino protecting group, it can be introduced by a general method. (R) -5-Benzyl-N-methyl-5-azaspiro [2.4] heptane-7-amine and 6-halo-7-deazapurine can be synthesized by those skilled in the art or purchased commercially. it can. The method may optionally further comprise a deprotection step when R7 is an amino protecting group.

  A compound of formula 9 or a salt thereof can be reacted with a compound of R4-L2 in a suitable solvent such as N, N-dimethylformamide to produce a compound of formula 2. For example, a compound of formula 9 or a salt thereof is reacted with 1-bromobutane in N, N-dimethylformamide at room temperature in the presence of N, N-diisopropylethylamine to give (R) -N- ( 5-Butyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine can be prepared.

  In said methods, the compounds of the invention are derived from starting materials that are readily available using general methods and processes or using other information readily available to those skilled in the art. Manufactured. See the Examples for more specific synthesis processes of the present invention.

  Compounds of the present invention, including compound salts and solvates including hydrates, are generally prepared using well-known organic synthesis techniques and synthesized by one of a number of possible synthetic routes. .

  The reaction for synthesizing the compound of the present invention is carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents are generally non-reactive with the starting material or reactant, intermediate or reaction product at the temperature at which the reaction is carried out, i.e., in the temperature range from the freezing point of the solvent to the boiling point of the solvent. A given reaction may also be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction stage, a solvent suitable for the specific reaction stage is selected.

  The synthesis of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups are readily determined by those skilled in the art.

  The reaction can be followed up by any suitable method known in the art. For example, the reaction product can be formed by spectroscopic methods such as nuclear magnetic resonance spectroscopy (eg, 1H or 13C), infrared spectroscopy, spectrophotometry (eg, UV-visible), and mass spectrometry, Follow-up observations can be made using chromatography such as performance liquid chromatography (HPLC) and thin layer chromatography (TLC). The compounds of the invention are synthesized by a number of synthetic routes well known in the literature.

  Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

  In this example, unless otherwise noted, reagents, starting materials and solvents are purchased from commercial suppliers (eg, Aldrich, Fluka, Sigma, Acros, Daejung Kay, TCI, etc.) without further purification. used. The purification used in the synthesis process proceeded via flash column chromatography using Merck Silica gel 60 (0.040-0.063 mm).

1. Intermediate Production Examples The compounds produced in the following examples were partially synthesized using the following intermediates.

(1.1) Intermediate 1: (R) -N- (5-Benzyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine -4-amine

In a 100 mL round bottom flask was charged 2.000 g of (R) -5-benzyl-N-methyl-5-azaspiro [2.4] heptan-7-amine (Sundia, China) with 40.0 mL of distilled water. I put it in. Thereafter, 1.490 g of 6-chloro-7-deazapurine (Acros) was added. To the reaction mixture, 2.560 g of potassium carbonate was added. The mixture was refluxed for 36 hours. After 36 hours, it was cooled at room temperature. The reaction mixture was extracted 3 times with 40.0 mL dichloromethane. The collected organic layer was concentrated under reduced pressure. The resulting residue was purified using flash column chromatography (MeOH: DCM = 2: 98).

  As a result, 2.370 g of (R) -N- (5-benzyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine-4 -The amine was obtained in a yield of 77.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.20 (s, 1H), 8.21 (s, 1H), 7.45-7.19 (m, 5H), 7.03 (s, 1H), 6.57 (s, 1H), 5.57 (s, 1H), 3.64 (dd, J = 31.2, 12.8 Hz, 2H), 3.52 (s, 3H), 2.95 ( s, 2H), 2.76 (d, J = 8.8 Hz, 1H), 2.51 (d, J = 8.8 Hz, 1H), 0.95 (d, J = 9.3 Hz, 1H), 0.63 (s, 2H), 0.47 (d, J = 9.7 Hz, 1H)

(1.2) Intermediate 2: (R) -N-methyl-N- (5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

In a 50 mL round bottom flask, 2.350 g of (R) -N- (5-benzyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] Pyrimidine-4-amine was added and dissolved in 25.0 mL of methanol. Then 2.350 g of 10 w / w% palladium / carbon (Acros) was charged and a hydrogen balloon was placed on top of the reaction flask. The reaction mixture was stirred vigorously for 39 hours. The reaction mixture was filtered through a filter agent Celite is a ^{(filter agent) 545 (Celite TM} 545) (Daejung gold) layer. The filtered solution was concentrated under reduced pressure.

  As a result, 1.510 g of (R) -N-methyl-N- (5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was converted into 88. Obtained in a yield of 0.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.77 (s, 1 H), 8.25 (s, 1 H), 7.07 (d, J = 3.5 Hz, 1 H), 6.58 (d, J = 3.5 Hz, 1 H), 5.38 (dd, J = 23.1, 16.5 Hz, 1 H), 3.72-3.56 (m, 1 H), 3.49 (d, J = 1.11. 7Hz, 4H), 3.30-3.11 (m, 2H), 2.92 (d, J = 11.2Hz, 1H), 0.93 (d, J = 10.9Hz, 1H),. 82-0.68 (m, 2H), 0.68-0.46 (m, 1H)

Example 1. (R) -N- (5-butyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

In a 5 mL round bottom flask, 70.0 mg of (R) -N-methyl-N- (5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4- The amine was added and dissolved with 1.0 mL N, N-dimethylformamide. To the solution was placed 59.3 mg of 1-bromobutane (Sigma-Aldrich). Thereafter, 0.100 mL of N, N-diisopropylethylamine (Daejung Kag) was added. The reaction solution was stirred overnight at ambient temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by column (MeOH: DCM = 2: 98). The resulting liquid separation was concentrated under reduced pressure and concentrated under vacuum. As a result, 35.0 mg of (R) -N- (5-butyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine-4 -The amine was obtained in 40.7% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.23 (s, 1H), 7.02 (s, 1H), 6.61 (s, 1H), 5.56 ( s, 1H), 3.49 (s, 3H), 2.96 (s, 2H), 2.78 (s, 1H), 2.52 (s, 3H), 1.53-1.51 (m) , 2H), 1.44-1.35 (m, 2H), 0.97 (t, J = 7.2 Hz, 4H), 0.74 (s, 2H), 0.51 (d, J = 9). .2Hz, 1H)
_{LRMS (ESI) calcd for (C} 17 H 25 N 5 + H +) 300.2, found 300.2

  The further compounds of the present invention described below were synthesized via methods analogous to those described in Example 1 described above.

Example 2 (R) -N-methyl-N- (5-pentyl-5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.29 (s, 1H), 8.20 (s, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 5.57 (s, 1H), 3.49 (s, 3H), 3.14-2.99 (m, 2H), 2.81 (s, 1H), 2. 57-2.48 (m, 3H), 1.71-1.66 (m, 4H), 1.37-1.33 (m, 2H), 0.97-0.91 (m, 4H), 0.79-0.66 (m, 2H), 0.55-0.50 (m, 1H)
_{LRMS (ESI) calcd for (C} 18 H 27 N 5 + H +) 314.2, found 314.2

Example 3 (R) -2-Methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 10.00 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.09-7.02 (M, 1H), 6.60-6.57 (m, 1H), 5.54-5.41 (m, 1H), 4.20-3.79 (m, 2H), 3.48-3 .38 (m, 4H), 2.74-2.59 (m, 1H), 1.20-1.15 (m, 6H), 1.10-1.01 (m, 1H), 0.90 -0.65 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 23 N 5 O + H +) 314.2, found 314.2

Example 4 (R) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (s, 1H), 8.25 (d, J = 3.2 Hz, 1H), 7.09-7.02 (m, 1H), 6.70 -6.59 (m, 1H), 5.52-5.44 (m, 1H), 4.16-4.07 (m, 1H), 3.99-3.85 (m, 3H), 3 .84-3.57 (m, 2H), 3.55-3.32 (m, 3H), 1.15-1.00 (m, 1H), 0.92-0.74 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 18 N 8 O + H +) 327.2, found 327.1

Example 5 FIG. (R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Nitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.24 (s, 1 H), 8.24 (d, J = 4.6 Hz, 1 H), 7.16-6.95 (m, 1 H), 6.57 (Dd, J = 7.2, 3.5 Hz, 1H), 5.63-5.34 (m, 1H), 4.27-4.02 (m, 1H), 4.01-3.83 ( m, 1H), 3.76 (dd, J = 11.4, 2.3 Hz, 1H), 3.51 (d, J = 12.4 Hz, 2H), 3.48-3.35 (m, 4H) ), 1.17-0.96 (m, 1H), 0.84 (ddd, J = 19.4, 10.7, 4.3 Hz, 3H)
LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2

Example 6 (R) -3-Methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) butane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.60 (D, J = 8.8 Hz, 1H), 5.47-5.36 (m, 1H), 4.16-3.74 (m, 3H), 3.49-3.38 (m, 4H) 2.29-2.18 (m, 3H), 1.09-0.98 (m, 7H), 0.90-0.73 (m, 3H)
LRMS (ESI) calcd for (C ₁₈ H ₂₅ N ₅ O + H ⁺ ) 328.2, found 328.2

Example 7 (R) -N- (2- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2 -Oxoethyl) acetamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.53 (d, J = 14.4 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.11 (s, 1H), 6 .72 (d, J = 18.4 Hz, 1H), 6.58 (s, 1H), 5.46 (dd, J = 31.6, 6.4 Hz, 1H), 4.13-4.06 ( m, 2H), 4.01-3.94 (m, 1H), 3.92-3.83 (m, 1H), 3.73 (d, J = 11.6 Hz, 1H), 3.52 ( d, J = 12.4 Hz, 1H), 3.43-3.40 (m, 3H), 2.07 (d, J = 4.0 Hz, 3H), 1.11-1.01 (m, 1H) ), 0.90-0.80 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 22 N 6 O 2 + H +) 343.2, found 343.1

Example 8 FIG. (R) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl)- 3-oxopropanamide

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 11.96 (d, J = 30.6Hz, 1H), 8.24 (dd, J = 6.6,1.8Hz, 1H), 8.13 (s, 1H), 7.11 (s, 1H), 6.54 (s, 1H), 5.51-5.34 (m, 1H), 4.13 (ddd, J = 21.2, 12.6, 7.5 Hz, 1H), 4.00-3.80 (m, 2H), 3.49 (t, J = 11.6 Hz, 1H), 3.40 (d, J = 14.5 Hz, 3H), 3.35 (t, J = 19.8 Hz, 2H), 2.83 (dd, J = 4.5, 2.1 Hz, 3H), 1.11-0.94 (m, 1H), 0.90 -0.68 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 22 N 6 O 2 + H +) 343.2, found 343.1

Example 9 (R) -Cyclopropyl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methaneone

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.32 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6 .59 (d, J = 11.6 Hz, 1H), 5.56-5.39 (m, 1H), 4.36-3.86 (m, 3H), 3.65-3.36 (m, 4H), 1.69-1.55 (m, 1H), 1.11-0.94 (m, 3H), 0.81-0.71 (m, 5H)
_{LRMS (ESI) calcd for (C} 17 H 21 N 5 O + H +) 312.2, found 312.1

Example 10 (R) -1- (4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) piperidine- 1-yl) ethane-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.80 (s, 1H), 8.28 (dd, J = 9.6, 3.2 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 5.49-5.40 (m, 1H), 4.64 (t, J = 12.4 Hz, 1H), 4.23- 4.02 (m, 1H), 4.00-3.78 (m, 3H), 3.52-3.49 (m, 1H), 3.46 (s, 3H), 3.39 (s, 1H), 3.15-3.10 (m, 1H), 2.66-2.56 (m, 2H), 2.13-2.04 (m, 3H), 1.88-1.70 ( m, 2H), 1.12-1.00 (m, 1H), 0.94-0.76 (m, 4H)
_{LRMS (ESI) calcd for (C} 21 H 28 N 6 O 2 + H +) 397.2, found 397.2

Example 11 (R) -Furan-2-yl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methaneone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.91 (s, 1H), 8.28 (s, 1H), 7.54 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H) ), 7.08 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 6.53 (s, 1H), 5.49 (d, J = 6.8 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.15-4.10 (m, 1H), 3.84-3.64 (m, 1H), 3.45 (s, 3H), 1.06 (s, 1H), 0.90-0.80 (m, 3H)
LRMS (ESI) calcd for (C ₁₈ H ₁₉ N ₅ O ₂ + H ⁺ ) 338.2, found 338.1

Example 12 (R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-3-yl) Methane on

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.27 (d, J = 25.2 Hz, 1H ), 7.91 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.05 (s, 1H), 6.61 (d, J = 21.6 Hz, 1H), 5.59-5.35 (m, 1H), 4.29-4.10 (m, 2H), 3.88-3.43 (m, 5H), 1.08-1.05 (m, 1H) ), 0.91-0.80 (m, 2H), 0.69 (s, 1H)
_{LRMS (ESI) calcd for (C} 19 H 20 N 6 O + H +) 349.2, found 349.2

Example 13 (R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 8.23 (d, J = 26.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7 .44 (s, 3H), 7.04 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 22.0 Hz, 1H), 5.47 (d, J = 78.0 Hz, 1H), 4.27-4.11 (m, 2H), 3.84-3.62 (m, 2H), 3.45 (d, J = 20.0 Hz, 3H), 1.05 (s, 1H), 0.89-0.66 (m, 3H)
_{LRMS (ESI) calcd for (C} 20 H 21 N 5 O + H +) 348.2, found 348.2

Example 14 (R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-4-yl) Methane on

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.49 (s, 1H), 8.75 (dd, J = 11.6, 5.6 Hz, 2H), 8.28 (d, J = 26.0 Hz, 1H), 7.42-7.41 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 17.6 Hz, 1H), 5.58- 5.36 (m, 1H), 4.31-4.08 (m, 2H), 3.77-3.42 (m, 5H), 1.08-1.05 (m, 1H),. 99-0.80 (m, 2H), 0.72-0.61 (m, 1H)
_{LRMS (ESI) calcd for (C} 19 H 20 N 6 O + H +) 349.2, found 349.1

Example 15. (R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 8.25 (d, J = 24.4 Hz, 1H), 7.86 (s, 1H), 7.82-7.73. (M, 2H), 7.58-7.54 (m, 1H), 7.07-7.02 (m, 1H), 6.61-6.57 (m, 1H), 5.60-5 .35 (m, 1H), 4.29-4.09 (m, 2H), 3.84-3.63 (m, 1H), 3.44-3.42 (m, 3H), 1.27 (S, 1H), 1.09-1.04 (m, 1H), 0.94-0.79 (m, 3H)
_{LRMS (ESI) calcd for (C} 21 H 20 N 6 O + H +) 373.2, found 373.1

Example 16 (R) -4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H), 8.28 (d, J = 26.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.67 (D, J = 8.0 Hz, 2H), 7.10 (d, J = 10.4 Hz, 1H), 6.60 (d, J = 20.4 Hz, 1H), 5.59 (m, 1H) 4.36-4.02 (m, 2H), 3.79-3.18 (m, 5H), 1.08-1.05 (m, 1H), 0.99-0.73 (m, 2H), 0.68 (s, 1H)
_{LRMS (ESI) calcd for (C} 21 H 20 N 6 O + H +) 373.2, found 373.2

Example 17. (R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (2- (trifluoromethyl ) Phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 8.35 (d, J = 32.4 Hz, 1H), 7.80-7.51 (m, 3H), 7.43 (D, J = 7.2 Hz, 1H), 7.08 (d, J = 9.6 Hz, 1H), 6.61 (d, J = 16.8 Hz, 1H), 5.63-5.36 ( m, 1H), 4.27-3.86 (m, 2H), 3.69-3.11 (m, 5H), 1.15-1.05 (m, 1H), 0.94-0. 81 (m, 2H), 0.75-0.54 (m, 1H)
_{LRMS (ESI) calcd for (C} 21 H 20 F 3 N 5 O + H +) 416.2, found 416.1

Example 18 (R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (3- (trifluoromethyl ) Phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 8.27 (d, J = 26.0 Hz, 1H), 7.84 (s, 1H), 7.76-7.70. (M, 2H), 7.61-7.56 (m, 1H), 7.09 (d, J = 10.4 Hz, 1H), 6.61 (d, J = 20.4 Hz, 1H), 5 .64-5.37 (m, 1H), 4.36-4.05 (m, 2H), 3.86-3.37 (m, 5H), 1.11 (d, J = 13.6 Hz, 1H), 0.99-0.69 (m, 3H)
_{LRMS (ESI) calcd for (C} 21 H 20 F 3 N 5 O + H +) 416.2, found 416.1

Example 19. (R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo Propanenitrile

¹ H NMR (400 MHz, CDCl 3) δ 12.07 (s, 1 H), 8.27 (d, J = 3.4 Hz, 1 H), 7.20-7.08 (m, 1 H), 6.57 ( dd, J = 5.7, 3.7 Hz, 1H), 5.45 (tt, J = 186.7, 93.9 Hz, 1H), 4.42-4.25 (m, 1H), 4.20 (Dd, J = 131.3, 13.0 Hz, 1H), 4.01 (dd, J = 162.4, 14.4 Hz, 1H), 3.98-3.85 (m, 2H), 3. 90 (dd, J = 211.1, 11.8 Hz, 1H), 3.44 (t, J = 19.7 Hz, 3H), 1.16-1.00 (m, 1H), 0.97-0 .74 (m, 3H)
_{LRMS (ESI) calcd for (C} 16 H 18 N 6 S + H +) 327.1, found 327.1

Example 20. Isobutyl (R) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.72 (s, 1H), 8.26 (s, 1H), 7.09 (s, 1H), 6.58 (s, 1H), 5.42 ( d, J = 5.6 Hz, 1H), 4.06-4.02 (m, 1H), 3.93 (d, J = 5.6 Hz, 2H), 3.81-3.72 (m, 2H) ), 3.43-3.34 (m, 4H), 2.01-1.91 (m, 1H), 1.02-0.88 (m, 7H), 0.78 (d, J = 9) .6Hz, 3H)
_{LRMS (ESI) calcd for (C} 18 H 25 N 5 O 2 + H +) 344.2, found 344.2

Example 21. (R) -N-butyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.20 (s, 1H), 8.25 (s, 1H), 7.09 (d, J = 3.3 Hz, 1H), 6.54 (s, 1H) ), 5.39 (d, J = 6.4 Hz, 1H), 4.36 (s, 1H), 3.97 (dd, J = 10.9, 7.4 Hz, 1H), 3.74 (d , J = 9.8 Hz, 1H), 3.65 (dd, J = 11.0, 1.6 Hz, 1H), 3.41 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 3.26 (dd, J = 13.2, 6.4 Hz, 2H), 1.66-1.42 (m, 2H), 1.35 (dq, J = 14.2, 7.3 Hz) , 2H), 0.99 (d, J = 9.2 Hz, 1H), 0.92 (dd, J = 7.8, 6.7 Hz, 3H), 0.75 (s, 3H)
_{LRMS (ESI) calcd for (C} 18 H 26 N 6 O + H +) 343.2, found 343.2

Example 22. (R) -N-cyclohexyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.87 (s, 1H), 8.26 (s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.11 (d, J = 7.8 Hz, 1H), 3.97 (dd, J = 10.9, 7.4 Hz, 1H), 3.74 (d, J = 9.9 Hz, 1H), 3.71-3.66 (m, 1H), 3.63 (dd, J = 11.0, 1.7 Hz) , 1H), 3.42 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 1.97 (d, J = 11.5 Hz, 2H), 1.69 (dd, J = 8.7, 4.1 Hz, 2H), 1.61 (d, J = 12.7 Hz, 1H), 1.37 (dd, J = 23.1, 11.4 Hz, 2H), 1.21- 1.0 3 (m, 3H), 0.99 (dd, J = 15.2, 8.0 Hz, 1H), 0.77 (s, 3H)
_{LRMS (ESI) calcd for (C} 20 H 28 N 6 O + H +) 369.2, found 369.2

Example 23. (R) -7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -N-phenyl-5-azaspiro [2.4] heptane-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.98 (s, 1H), 8.27 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.27 (dd, J = 9.1, 6.7 Hz, 2H), 7.09 (d, J = 3.3 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 6.44 (s, 1H), 5.42 (d, J = 6.5 Hz, 1H), 4.09 (dd, J = 10.9, 7.5 Hz, 1H), 3.86 (d, J = 10.0 Hz, 1H), 3.82-3.73 (m, 1H), 3.45 (s, 1H), 3.43 (s, 3H), 1.08- 0.99 (m, 1H), 0.78 (s, 3H)
_{LRMS (ESI) calcd for (C} 20 H 22 N 6 O + H +) 363.2, found 363.2

Example 24. (R) -N- (4-Fluorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.27 (s, 1H), 7.40-7.37 (m, 2H), 7.10-7.09 (m , 1H), 7.03-6.99 (m, 2H), 6.61 (s, 1H), 6.19 (s, 1H), 5.46 (d, J = 5.6 Hz, 1H), 4.15 (dd, J = 10.8, 7.2 Hz, 1H), 3.91 (d, J = 10.0 Hz, 1H), 3.81 (dd, J = 11.2, 2.0 Hz, 1H), 3.48-3.46 (m, 4H), 1.11-1.02 (m, 1H), 0.90-0.84 (m, 3H)
LRMS (ESI) calcd for (C ₂₀ H ₂₁ FN ₆ O + H ⁺ ) 381.2, found 381.2

Example 25. (R) -N- (2,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1 H), 8.32 (d, J = 9.2 Hz, 1 H), 8.27 (s, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 7.27-7.24 (m, 1 H), 7.10 (t, J = 2.8 Hz, 1 H), 6.83 (s, 1 H), 6.61 (s) , 1H), 5.53 (d, J = 6.4 Hz, 1H), 4.20 (dd, J = 11.2, 7.6 Hz, 1H), 3.92 (d, J = 9.6 Hz, 1H), 3.85 (d, J = 10.0 Hz, 1H), 3.50 (m, 4H), 1.11 (d, J = 11.2 Hz, 1H), 0.90-0.85 ( m, 3H)
_{LRMS (ESI) calcd for (C} 20 H 20 Cl 2 N 6 O + H +) 431.1, found 431.1

Example 26. (R) -N- (3,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 8.27 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1 H), 7.27 (d, J = 2.8 Hz, 1 H), 7.10-7.09 (m, 1 H), 6.61 (d, J = 2.0 Hz, 1 H) 6.26 (s, 1H), 5.45 (d, J = 5.6 Hz, 1H), 4.14 (dd, J = 10.8, 7.2 Hz, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.48 (s, 3H), 3.46 (s, 1H), 1.09-1.06 ( m, 1H), 0.90-0.85 (m, 3H)
_{LRMS (ESI) calcd for (C} 20 H 20 Cl 2 N 6 O + H +) 431.1, found 431.1

Example 27. (R) -N- (2,5-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.92 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 7.27 (s, 1H ), 7.09 (t, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 6.89 (s, 1H), 6.62 (d , J = 1.6 Hz, 1H), 5.55 (d, J = 6.4 Hz, 1H), 4.19 (dd, J = 11.2, 7.6 Hz, 1H), 3.92 (d, J = 10.0 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.51 (s, 1H), 3.49 (s, 3H), 1.10 (d, J = 11.2Hz, 1H), 0.94-0.85 (m, 3H)
_{LRMS (ESI) calcd for (C} 20 H 20 Cl 2 N 6 O + H +) 431.1, found 431.1

Example 28. (R) -N- (2,3-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.03 (s, 1H), 8.39-8.21 (m, 2H), 7.19 (t, J = 8.2 Hz, 1H), 7.13 (Dd, J = 3.9, 3.3 Hz, 2H), 6.97 (s, 1H), 6.58 (d, J = 3.4 Hz, 1H), 5.55 (d, J = 6. 3Hz, 1H), 4.17 (dd, J = 111.2, 7.5Hz, 1H), 3.88 (dd, J = 22.4, 10.5Hz, 2H), 3.50 (s, 1H) ), 3.47 (s, 3H), 1.14-1.01 (m, 1H), 0.84 (s, 3H)
_{LRMS (ESI) calcd for (C} 20 H 20 Cl 2 N 6 O + H +) 431.1, found 431.0

Example 29. (R) -N- (3-Chloro-4-methylphenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.92 (s, 1H), 8.25 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1 H), 7.08 (s, 1 H), 7.06 (d, J = 5.2 Hz, 1 H), 6.56 (s, 1 H), 6.53 (d , J = 3.4 Hz, 1H), 5.39 (d, J = 6.2 Hz, 1H), 4.06 (dd, J = 11.1, 7.4 Hz, 1H), 3.82 (d, J = 10.1 Hz, 1H), 3.77 (dd, J = 11.1, 1.5 Hz, 1H), 3.46-3.35 (m, 4H), 2.28 (s, 3H), 1.05-0.96 (m, 1H), 0.82-0.71 (m, 3H)
LRMS (ESI) calcd for (C ₂₁ H ₂₃ ClN ₆ O + H ⁺ ) 411.2, found 411.1

Example 30. FIG. (R) -N-([1,1′-biphenyl] -2-yl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2 .4] Heptane-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.27 (s, 1H), 8.24 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.51-7.30 (M, 6H), 7.21 (d, J = 7.2 Hz, 1H), 7.10 (dd, J = 9.2, 5.5 Hz, 2H), 6.55 (d, J = 2. 9 Hz, 1H), 6.38 (s, 1H), 5.34 (d, J = 6.4 Hz, 1H), 3.82 (dd, J = 10.9, 7.5 Hz, 1H), 3. 64 (d, J = 10.0 Hz, 1H), 3.48 (d, J = 10.1 Hz, 1H), 3.38 (s, 3H), 3.20 (d, J = 9.9 Hz, 1H) ), 1.04-0.95 (m, 1H), 0.78-0.59 (m, 3H)
_{LRMS (ESI) calcd for (C} 26 H 26 N 6 O + H +) 439.2, found 439.2

Example 31. (R) -N- (3,5-bis (trifluoromethyl) phenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2. 4] Heptane-5-carbothioamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.64 (s, 1H), 8.25 (s, 1H), 7.96 (s, 2H), 7.65 (s, 1H), 7.41 ( s, 1H), 7.10 (d, J = 3.4 Hz, 1H), 6.57 (d, J = 3.4 Hz, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.31 (s, 1H), 4.17 (s, 1H), 4.08 (s, 1H), 3.75 (s, 1H), 3.46 (s, 3H), 1.05 (d , J = 5.7 Hz, 1H), 0.87 (d, J = 8.1 Hz, 3H)
_{LRMS (ESI) calcd for (C} 22 H 20 F 6 N 6 S + H +) 515.1, found 515.1

Example 32. (R) -N-methyl-N- (5-((trifluoromethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 -Amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.34 (s, 1H), 8.26 (s, 1H), 7.12 (s, 1H), 6.61 (s, 1H), 5.56 ( dd, J = 7.6, 3.2 Hz, 1H), 4.19 (dd, J = 11.6, 7.6 Hz, 1H), 3.93-3.85 (m, 2H), 3.53 -3.49 (m, 4H), 1.12-1.05 (m, 1H), 0.89-0.83 (m, 3H)
_{LRMS (ESI) calcd for (C} 14 H 16 F 3 N 5 O 2 S + H +) 376.1, found 376.1

Example 33. (R) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.53 (s, 1H), 8.25 (s, 1H), 7.10-7.09 (m, 1H), 6.61 (s, 1H), 5.58 (dd, J = 5.3, 2.8 Hz, 1H), 3.96 (dd, J = 11.2, 7.6 Hz, 1H), 3.72-3.68 (m, 2H) 3.50 (s, 3H), 3.37 (d, J = 9.6 Hz, 1H), 3.12 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7. 4Hz, 3H), 1.10-1.03 (m, 1H), 0.86-0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 21 N 5 O 2 S + H +) 336.2, found 336.1

Example 34. (R) -N- (5- (isopropylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 8.25 (s, 1H), 7.07 (s, 1H), 6.60 (s, 1H), 5.53 ( d, J = 4.4 Hz, 1H), 4.01 (dd, J = 11.2, 7.6 Hz, 1H), 3.77-3.71 (m, 2H), 3.49 (s, 3H) ), 3.40 (d, J = 9.6 Hz, 1H), 3.33-3.27 (m, 1H), 1.44 (d, J = 6.4 Hz, 6H), 1.11-1 .01 (m, 1H), 0.90-0.75 (m, 3H)
_{LRMS (ESI) calcd for (C} 16 H 23 N 5 O 2 S + H +) 350.2, found 350.2

Example 35. (R) -N-methyl-N- (5- (propylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 8.25 (s, 1H), 7.09 (s, 1H), 6.60 (s, 1H), 5.82- 5.55 (m, 1H), 3.92 (dd, J = 10.8, 7.6 Hz, 1H), 3.70-3.67 (m, 2H), 3.50 (s, 3H), 3.35 (d, J = 10.0 Hz, 1H), 3.05-3.01 (m, 2H), 2.06-1.90 (m, 2H), 1.13 (t, J = 7 .6 Hz, 3H), 1.07-1.02 (m, 1H), 0.86-0.71 (m, 3H)
_{LRMS (ESI) calcd for (C} 16 H 23 N 5 O 2 S + H +) 350.2, found 350.1

Example 36. (R) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.74-7.57. (M, 3H), 7.05 (s, 1H), 6.56 (s, 1H), 5.45 (t, J = 5.0 Hz, 1H), 3.68-3.59 (m, 2H) ), 3.57 (d, J = 5.6 Hz, 1H), 3.36 (s, 3H), 3.10 (d, J = 9.6 Hz, 1H), 0.93-0.87 (m) , 1H), 0.84-0.72 (m, 1H), 0.67-0.59 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 21 N 5 O 2 S + H +) 384.2, found 384.1

Example 37. (R) -N- (5-((2-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.52 (s, 1H), 8.19 (s, 1H), 7.95-7.91 (m, 1H), 7.66-7.61 (m , 1H), 7.34-7.25 (m, 2H), 7.25 (s, 1H), 6.57 (s, 1H), 5.49-5.46 (m, 1H), 3. 85 (dd, J = 11.2, 7.6 Hz, 1H), 3.72-3.69 (m, 2H), 3.43 (s, 3H), 3.30 (d, J = 9.6 Hz) , 1H), 0.98-0.88 (m, 1H), 0.82-0.77 (m, 1H), 0.74-0.65 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 20 FN 5 O 2 S + H +) 402.1, found 402.1

Example 38. (R) -N- (5-((3-Fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.18 (s, 1H), 7.67-7.54 (m, 3H), 7.40-7.33 (m , 1H), 7.06-7.02 (m, 1H), 6.57-6.56 (m, 1H), 5.46-5.44 (m, 1H), 3.65-3.62 (M, 2H), 3.59 (d, J = 9.6 Hz, 1H), 3.38 (s, 3H), 3.12 (d, J = 9.6 Hz, 1H), 0.96-0 .91 (m, 1H), 0.80-0.74 (m, 1H), 0.69-0.68 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 20 FN 5 O 2 S + H +) 402.1, found 402.1

Example 39. (R) -N- (5-((4-Fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (s, 1H), 8.18 (s, 1H), 7.94-7.85 (m, 2H), 7.27-7.24 (m , 2H), 7.06 to 6.99 (m, 1H), 6.57 to 6.55 (m, 1H), 5.46 (dd, J = 6.4, 1.6 Hz, 1H), 3 .71-3.53 (m, 3H), 3.38 (s, 3H), 3.09 (d, J = 9.6 Hz, 1H), 0.95-0.88 (m, 1H), 0 .82-0.74 (m, 1H), 0.69-0.60 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 20 FN 5 O 2 S + H +) 402.1, found 402.1

Example 40. (R) -2-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.19 (s, 1H), 8.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (Dd, J = 7.2, 1.2 Hz, 1H), 7.81-7.73 (m, 2H), 7.08-7.02 (m, 1H), 6.58-6.56 ( m, 1H), 5.52 (dd, J = 7.6, 6.8 Hz, 1H), 3.85-3.74 (m, 2H), 3.72 (dd, J = 10.8, 3 .0Hz, 1H), 3.43 (s, 3H), 3.41 (d, J = 10.0 Hz, 1H), 1.06-0.94 (m, 1H), 0.88-0.69 (M, 3H)
_{LRMS (ESI) calcd for (C} 20 H 20 N 6 O 2 S + H +) 409.1, found 409.1

Example 41. (R) -3-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.09-8.07 (m, 1H), 7.95-7.93 (m, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.08-7.02 (m, 1H), 6.56-6.55 (m , 1H), 5.44-5.32 (m, 1H), 3.69-3.61 (m, 3H), 3.39 (s, 3H), 3.13 (d, J = 9.6 Hz) , 1H), 0.98-0.88 (m, 1H), 0.84-0.77 (m, 1H), 0.73-0.63 (m, 2H)
_{LRMS (ESI) calcd for (C} 20 H 20 N 6 O 2 S + H +) 409.1, found 409.1

Example 42. (R) -4-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.99 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 6.55 (s, 1H), 5.39-5.37 (m, 1H), 3.68-3.65 (m, 2H) ), 3.62 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H), 3.13 (d, J = 9.6 Hz, 1H), 0.99-0.91 (m) , 1H), 0.85-0.74 (m, 1H), 0.72-0.62 (m, 2H)
_{LRMS (ESI) calcd for (C} 20 H 20 N 6 O 2 S + H +) 409.1, found 409.1

Example 43. (R) -N-methyl-N- (5-((2-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (s, 1H), 8.22 (s, 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.78 −7.66 (m, 3H), 7.07 (t, J = 2.4 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 5.52 (dd, J = 7. 6, 2.4 Hz, 1H), 3.96 (dd, J = 10.8, 7.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.43 (s, 3H), 3.41 (s, 1H), 1.03-0.99 (m, 1H), 0.92-0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 19 H 20 N 6 O 4 S + H +) 429.1, found 429.1

Example 44. (R) -N-methyl-N- (5-((3-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 8.22 (s, 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.78 −7.66 (m, 3H), 7.07 (t, J = 2.4 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 5.52 (dd, J = 7. 6, 2.4 Hz, 1H), 3.96 (dd, J = 10.8, 7.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.43 (s, 3H), 3.41 (s, 1H), 1.03-0.99 (m, 1H), 0.92-0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 19 H 20 N 6 O 4 S + H +) 429.1, found 429.1

Example 45. (R) -N-methyl-N- (5-((4-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 8.19 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.07 (t, J = 2.4 Hz, 1H), 6.53 (t, J = 1.6 Hz, 1H), 5.39-5.36 (m, 1H) 3.72-3.67 (m, 2H), 3.64 (d, J = 9.6 Hz, 1H), 3.38 (s, 3H), 3.14 (d, J = 9.6 Hz, 1H), 0.96-0.89 (m, 1H), 0.88-0.79 (m, 1H), 0.75-0.63 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 20 N 6 O 4 S + H +) 429.1, found 429.1

Example 46. (R) -N-methyl-N- (5- (m-tolylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.19 (s, 1H), 7.66 (s, 2H), 7.47-7.46 (m, 2H), 7.06 (s, 1H), 6.55 (s, 1H), 5.45-5.43 (m, 1H), 3.61-3.52 (m, 3H), 3.37 (s, 3H), 3.10-3.07 (d, J = 9.6 Hz, 1H), 2.46 (s, 3H), 0.93-0.88 (m, 1H), 0.79-0. 73 (m, 1H), 0.67-0.59 (m, 2H)
_{LRMS (ESI) calcd for (C} 20 H 23 N 5 O 2 S + H +) 398.2, found 398.1

Example 47. (R) -N- (5-((4-methoxyphenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 3H), 6.61 (s, 1H), 5.46 (s, 1H), 3.92 (s, 3H), 3.61-3.55 (m, 2H), 3. 53 (m, 1H), 3.38 (s, 3H), 3.07 (d, J = 9.6 Hz, 1H), 0.94-0.90 (m, 1H), 0.82-0. 72 (m, 1H), 0.66-0.59 (m, 2H)
_{LRMS (ESI) calcd for (C} 20 H 23 N 5 O 3 S + H +) 414.2, found 414.1

Example 48. (R) -N-methyl-N- (5-((4- (trifluoromethyl) phenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3- d] pyrimidine-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.54 (s, 1H), 5.43-5.32 (m, 1H), 3.69-3.58 (m, 3H) ), 3.37 (s, 3H), 3.13 (d, J = 9.60 Hz, 1H), 0.97-0.88 (m, 1H), 0.81-0.75 (m, 1H) ), 0.71-0.62 (m, 2H)
_{LRMS (ESI) calcd for (C} 20 H 20 F 3 N 5 O 2 S + H +) 452.1, found 452.1

Example 49. (R) -N-methyl-N- (5- (naphthalen-2-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 -Amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 8.03-7.96 (m, 3H), 7.87 (dd, J = 8.8, 5.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.03 (s, 1H), 6.57 (s, 1H), 5.54-5.41 (m, 1H), 3.75-3.63 (m, 2H), 3.62 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H), 3.17 (d, J = 9.6 Hz, 1H), 0.90-0.84 (m, 1H), 0.78-0.72 (m, 1H), 0.68-0.57 (m , 2H)
_{LRMS (ESI) calcd for (C} 23 H 23 N 5 O 2 S + H +) 434.2, found 434.1

Example 50. (R) -N-methyl-N- (5- (piperidin-1-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 -Amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.81 (s, 1H), 8.24 (s, 1H), 7.07-7.00 (m, 1H), 6.60-6.59 (m , 1H), 5.52 (d, J = 5.2 Hz, 1H), 3.87 (dd, J = 10.8, 7.6 Hz, 1H), 3.57-3.54 (m, 2H) 3.49 (s, 3H), 3.31-3.28 (m, 4H), 1.81-1.58 (m, 7H), 1.04-1.01 (m, 1H), 0 .82-0.74 (m, 2H), 0.71-0.68 (m, 1H)
_{LRMS (ESI) calcd for (C} 18 H 26 N 6 O 2 S + H +) 391.2, found 391.1

Example 51. (R) -N-methyl-N- (5- (morpholinosulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 8.25 (s, 1H), 7.08-7.07 (m, 1H), 6.65-6.59 (m , 1H), 5.58 (dd, J = 7.6, 2.8 Hz, 1H), 3.93 (dd, J = 10.8, 7.6 Hz, 1H), 3.78 (t, J = 4.8 Hz, 4H), 3.65-3.59 (m, 2H), 3.48 (s, 3H), 3.34-3.30 (m, 5H), 1.10-1.02 ( m, 1H), 0.83-0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 24 N 6 O 3 S + H +) 393.2, found 393.1

Example 52.1- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 8.32-8.16 (m, 1H), 7.07 (s, 1H), 6.57 (s, 1H), 5.63-5.31 (m, 1H), 4.19-3.97 (m, 2H), 3.97-3.66 (m, 2H), 3.55-3.43 (m, 1H) ), 3.43-3.26 (m, 3H), 2.32 (dq, J = 14.4, 7.3 Hz, 1H), 1.23-1.12 (m, 2H), 1.10 -0.93 (m, 1H), 0.91-0.63 (m, 3H)
LRMS (ESI) calcd for (C ₁₆ H ₂₁ N ₅ O + H ⁺ ) 300.2, found 300.3

Example 53. 2-Methoxy-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.09 (s, 1 H), 8.23 (s, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.57 (d, J = 3.1 Hz, 1H), 5.38 (d, J = 5.7 Hz, 1H), 4.07 (d, J = 7.5 Hz, 1H), 3.96 (dd, J = 11.0, 7.4 Hz, 1H), 3.73 (d, J = 9.9 Hz, 1H), 3.62 (dd, J = 11.0, 2.2 Hz, 1H), 3.42 (s, 3H), 1.4-1.30 (m, 2H), 1.21-1.04 (m, 3H), 1.03-0.95 (m, 1H), 0.84-0.68 (m, 3H) )
_{LRMS (ESI) calcd for (C} 16 H 21 N 5 O 2 + H +) 316.2, found 316.1

Example 54.2-Azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.98 (s, 1H), 8.37-8.03 (m, 1H), 7.17-6.97 (m, 1H), 6.69-6 .45 (m, 1H), 5.63-5.32 (m, 1H), 4.15-4.00 (m, 1H), 3.99-3.75 (m, 3H), 3.69 -3.48 (m, 2H), 3.48-3.27 (m, 3H), 1.04-0.93 (m, 1H), 0.91-0.64 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 18 N 8 O + H +) 327.2, found 327.2

Example 55.3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Nitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 7.15-7.03 (m, 1H), 6.61 (S, 1H), 5.58-5.35 (m, 1H), 4.26-4.03 (m, 1H), 4.02-3.91 (m, 1H), 3.89-3 .72 (m, 1H), 3.72-3.51 (m, 2H), 3.48 (d, J = 7.7 Hz, 2H), 3.45-3.32 (m, 2H), 1 19-0.99 (m, 1H), 0.95-0.68 (m, 3H)
LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2

Example 56. N- (2- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl) acetamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.18 (d, J = 14.5 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 7.08 (dd, J = 18. 0, 14.6 Hz, 1H), 6.68 (d, J = 17.3 Hz, 1H), 6.58 (d, J = 3.1 Hz, 1H), 5.55-5.35 (m, 1H) ), 4.17-4.03 (m, 2H), 4.03-3.93 (m, 1H), 3.87 (dd, J = 27.0, 11.3 Hz, 1H), 3.78 -3.68 (m, 1H), 3.57-3.48 (m, 1H), 3.46-3.33 (m, 3H), 2.08 (d, J = 4.2 Hz, 3H) 1.14 to 0.97 (m, 1H), 0.94 to 0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 22 N 6 O 2 + H +) 343.2, found 343.2.

Example 57. N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Amide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.89 (s, 1H), 8.24 (d, J = 4.2 Hz, 1H), 8.08 (s, 1H), 7.17-7.05 (M, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.43 (t, J = 7.8 Hz, 1H), 5.30 (s, 1H), 4.13 (ddd , J = 21.2, 12.7, 7.5 Hz, 1H), 3.91 (dd, J = 46.8, 11.7 Hz, 1H), 3.99-3.81 (m, 1H), 3.49 (t, J = 11.0 Hz, 1H), 3.42 (s, 1H), 3.37 (t, J = 10.0 Hz, 3H), 2.84 (dd, J = 4.7) , 2.5 Hz, 3H), 1.10-0.95 (m, 1H), 0.89-0.72 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 22 N 6 O 2 + H +) 343.2, found 343.1

Example 58.3-Amino-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propane -1-one

¹ H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.08 (d, J = 3.1 Hz, 1H), 7.92 (s, 2H), 7.17 (d, J = 2.4 Hz, 1H), 6.61 (s, 1H), 5.39-5.06 (m, 1H), 4.20-3.57 (m, 3H), 3.32-3.24 ( m, 4H), 3.11-2.90 (m, 2H), 2.87-2.56 (m, 2H), 0.96-0.68 (m, 3H), 0.68-0. 44 (m, 1H)
_{LRMS (ESI) calcd for (C} 16 H 22 N 6 O + H +) 315.2, found 315.2

Example 59. 2- (1H-imidazol-1-yl) -1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4 ] Heptane-5-yl) ethane-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7 20-6.96 (m, 3H), 6.60 (d, J = 10.0 Hz, 1H), 5.60-5.35 (m, 1H), 4.75 (d, J = 6. 7Hz, 2H), 4.02-3.88 (m, 1H), 3.77 (dd, J = 27.1, 10.8Hz, 1H), 3.59-3.49 (m, 1H), 3.49-3.30 (m, 3H), 1.18-1.08 (m, 1H), 1.08-0.96 (m, J = 9.5 Hz, 1H), 0.96-0 .72 (m, 3H)
_{LRMS (ESI) calcd for (C} 18 H 21 N 7 O + H +) 352.2, found 352.1

Example 60.3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo Propanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.35 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.16-7.07 (m, 1H), 6.58 (Dd, J = 5.6, 3.7 Hz, 1H), 5.52 (ddd, J = 9.0, 7.3, 2.4 Hz, 1H), 4.44-4.20 (m, 2H) ), 4.11 (dd, J = 55.2, 12.4 Hz, 1H), 3.91 (d, J = 9.3 Hz, 2H), 3.73 (dd, J = 68.2, 12. 8Hz, 1H), 3.42 (d, J = 22.7Hz, 3H), 1.18-1.01 (m, 1H), 0.98-0.75 (m, 3H)
_{LRMS (ESI) calcd for (C} 16 H 18 N 6 S + H +) 327.1, found 327.1

Example 61. Isobutyl 7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (s, 1H), 8.24 (s, 1H), 7.05 (s, 1H), 6.59 (s, 1H), 5.40 ( s, 1H), 4.04 (dd, J = 12.3, 7.5 Hz, 1H), 3.92 (d, J = 5.3 Hz, 2H), 3.85-3.62 (m, 2H) ), 3.51-3.23 (m, 4H), 2.05-1.86 (m, 1H), 1.13-0.86 (m, 7H), 0.77 (d, J = 8) .0Hz, 3H)
_{LRMS (ESI) calcd for (C} 18 H 25 N 5 O 2 + H +) 344.2, found 344.1

Example 62. N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.01 (s, 1H), 8.24 (s, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1 H), 5.57 (dd, J = 7.5, 3.1 Hz, 1 H), 3.94 (dd, J = 11.0, 7.5 Hz, 1 H), 3.74− 3.64 (m, 2H), 3.55-3.47 (m, 3H), 3.36 (d, J = 9.8 Hz, 1H), 3.16-3.04 (m, 2H), 1.45 (t, J = 7.4 Hz, 3H), 1.10-1.03 (m, 1H), 0.86-0.71 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 21 N 5 O 2 S + H +) 336.2, found 336.2

Example 63. N- (5-((2-aminoethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.81 (s, 1H), 8.24 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1 H), 5.54 (dd, J = 7.4, 2.9 Hz, 1 H), 3.92 (dd, J = 11.0, 7.6 Hz, 1 H), 3.76− 3.59 (m, 2H), 3.48 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 3.30-3.22 (m, 2H), 3.22- 3.02 (m, 2H), 1.88 (s, 2H), 1.04 (dd, J = 7.3, 4.2 Hz, 1H), 0.91-0.58 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 22 N 6 O 2 S + H +) 351.2, found 351.2

Example 64. FIG. (S) -1- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.49 (s, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H) ), 5.48-5.32 (m, 1H), 4.18-3.98 (m, 1H), 3.82 (ddd, J = 47.3, 32.5, 11.5 Hz, 2H) 3.51-3.28 (m, 4H), 2.32 (td, J = 14.9, 7.6 Hz, 2H), 1.27 (d, J = 9.7 Hz, 1H), 22-1.11 (m, 2H), 1.11-0.93 (m, 1H), 0.93-0.61 (m, 3H)
LRMS (ESI) calcd for (C ₁₆ H ₂₁ N ₅ O + H ⁺ ) 300.2, found 300.1

Example 65. (S) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 23.7 Hz, 1H), 6 .66-6.45 (m, 1H), 5.43 (dd, J = 47.4, 5.3 Hz, 1H), 4.15-4.01 (m, 1H), 3.99-3. 74 (m, 3H), 3.58 (dd, J = 58.3, 11.9 Hz, 1H), 3.46-3.31 (m, 4H), 1.13-0.94 (m, 1H) ), 0.92-0.66 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 18 N 8 O + H +) 327.2, found 327.2

Example 66. (S) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Nitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.37 (s, 1H), 8.26 (d, J = 4.5 Hz, 1H), 7.16-7.02 (m, 1H), 6.57 (Dd, J = 7.0, 3.5 Hz, 1H), 5.45 (ddd, J = 38.6, 7.3, 2.3 Hz, 1H), 4.14 (ddd, J = 21.4) , 12.5, 7.5 Hz, 1H), 3.91 (t, J = 11.5 Hz, 1H), 3.85 (ddd, J = 13.7, 12.7, 2.6 Hz, 1H), 3.48 (q, J = 13.5 Hz, 1H), 3.45 (s, 3H), 3.39 (s, 2H), 1.14-0.98 (m, 1H), 0.92- 0.73 (m, 3H)
LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2

Example 67. (S) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl)- 3-oxopropanamide

¹ H NMR (500 MHz, CDCl ₃ ) δ 11.85 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 1.11. 0 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.55 (s, 1H), 5.43 (dd, J = 16.7, 6.3 Hz, 1H), 4. 13 (ddd, J = 21.1, 12.5, 7.5 Hz, 1H), 4.00-3.81 (m, 2H), 3.49 (t, J = 11.4 Hz, 1H), 3 .40 (d, J = 18.6 Hz, 3H), 3.37 (d, J = 29.0 Hz, 2H), 2.86 (t, J = 11.0 Hz, 3H), 1.09-0. 97 (m, 1H), 0.86-0.69 (m, 3H)
_{LRMS (ESI) calcd for (C} 17 H 22 N 6 O 2 + H +) 343.2, found 343.1

Example 68. (S) -4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (s, 1H), 8.24 (d, J = 27.2 Hz, 1H), 7.85-7.55 (m, 4H), 7.07 (D, J = 7.4 Hz, 1H), 6.59 (d, J = 19.0 Hz, 1H), 5.64-5.34 (m, 1H), 4.37-4.03 (m, 2H), 3.84-3.27 (m, 5H), 1.16-1.00 (m, 1H), 0.98-0.60 (m, 3H)
_{LRMS (ESI) calcd for (C} 21 H 20 N 6 O + H +) 373.2, found 373.2

Example 69. (S) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo Propanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.13 (s, 1H), 8.18 (s, 1H), 7.11-6.97 (m, 1H), 6.59-6.44 (m , 1H), 5.56-5.34 (m, 1H), 4.38-3.92 (m, 3H), 3.92-3.78 (m, 2H), 3.66 (dd, J = 67.4, 13.0 Hz, 1H), 3.36 (d, J = 22.9 Hz, 3H), 1.09-0.94 (m, 1H), 0.91-0.58 (m, 3H)
_{LRMS (ESI) calcd for (C} 16 H 18 N 6 S + H +) 327.1, found 327.1

Example 70. Isobutyl (S) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.26 (s, 1H), 8.25 (s, 1H), 7.07 (d, J = 3.2 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 5.51-5.50 (m, 1H), 4.11-4.04 (m, 1H), 3.93 (d, J = 1.2 Hz, 2H), 3 .91-3.74 (m, 2H), 3.42-3.38 (m, 4H), 2.01-1.90 (m, 1H), 1.01-0.95 (m, 7H) 0.77-0.75 (d, J = 10.0 Hz, 3H)
_{LRMS (ESI) calcd for (C} 18 H 25 N 5 O 2 + H +) 344.2, found 344.3

Example 71. (S) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, 1 H), 8.23 (s, 1 H), 7.07 (d, J = 3.1 Hz, 1 H), 6.58 (d, J = 3.4 Hz, 1 H), 5.55 (dd, J = 7.5, 3.0 Hz, 1 H), 3.92 (dd, J = 11.0, 7.6 Hz, 1 H), 3.80− 3.57 (m, 2H), 3.48 (s, 3H), 3.33 (d, J = 9.8 Hz, 1H), 3.08 (q, J = 7.4 Hz, 2H), 43 (t, J = 7.4 Hz, 3H), 1.11-0.90 (m, 1H), 0.90-0.60 (m, 3H)
_{LRMS (ESI) calcd for (C} 15 H 21 N 5 O 2 S + H +) 336.2, found 336.1

Example 72. (S) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 8.16 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 6.9 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 2 H), 7.04 (s, 1 H), 6.53 (s, 1 H), 5.46-5.36 (m) , 1H), 3.68-3.56 (m, 2H), 3.52 (d, J = 9.6 Hz, 1H), 3.34 (s, 3H), 3.07 (d, J = 9 .5Hz, 1H), 0.93-0.83 (m, 1H), 0.78-0.68 (m, 1H), 0.65-0.55 (m, 2H)
_{LRMS (ESI) calcd for (C} 19 H 21 N 5 O 2 S + H +) 384.2, found 384.0

Example 73. (R) -N- (5-ethyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 8.29 (s, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 5.57 (s, 1H), 3.47 (s, 3H), 3.16 (s, 1H), 3.03 (s, 1H), 2.92 (d, J = 7.6 Hz, 1H), 2.66 (d, J = 9.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.98-0.94 (m, 1H) ), 0.77-0.68 (m, 2H), 0.55-0.53 (m, 1H)
_{LRMS (ESI) calcd for (C} 15 H 21 N 5 + H +) 272.2, found 272.1

Example 74: Effect of a compound of formula 1 as a JAK inhibitor Test Tuberase Phosphate Enzyme Inhibition Method (1) Phosphorylase diluted kinase (kinase) uses human-derived JAK1, JAK2, JAK3, and TYK2 (Millipore, Germany). Separately diluted in a suitable buffer and mixed with the reaction reagent.
(1.1) Composition of JAK1 dilution buffer In distilled water, tris (hydroxymethyl) aminomethane (TRIS) and ethylenediaminetetraacetic acid (EDTA) are 20 mM and 0.2 mM, respectively. 100 mL standard 100 μL β-mercaptoethanol, 10 μL Brij-35 ^TM and 5 mL glycerol were added to prepare a JAK1 dilution buffer.
(1.2) Composition of JAK2, JAK3 and TYK2 dilution buffer In distilled water, 3-morpholinopropane-1-sulfonic acid (MOPS) and EDTA are 20 mM and 1 mM, respectively. 100 mL standard 100 μL β-mercaptoethanol, 10 μL Brij-35 ^™ , 5 mL glycerol and 100 mg BSA were added to prepare JAK2, JAK3 and TYK2 dilution buffers.
(2) Compound Preparation and Experimental Method All compounds are dissolved in 100% DMSO solution at a concentration of 50 μM. The solution thus prepared was reacted with a reaction reagent in each well of a 96-well plate, but the final concentration was 1 μM. Detailed experimental methods for each phosphorylating enzyme are as follows.
(2.1) JAK1
The final concentration of the substance contained in the 25 μL reaction solution is as shown in Table 1 below.
As γ- ³³ P-ATP, one produced from non-radiolabelled ATP (Sigma, Cat. no. A-7699) was used. After reacting at room temperature for 40 minutes, 5 μL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After completion of the reaction, 10 μL of the solution was instilled into GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed 3 times with 75 mM phosphoric acid solution for 5 minutes. Methanol drying was performed and scintillation was measured. Methanol drying means adding methanol to an aqueous solution and drying using the azeotrope effect.
(2.2) JAK2
The final concentrations of the substances contained in the 25 μL reaction solution are as shown in Table 2 below.
As γ- ³³ P-ATP, one produced from non-radiolabelled ATP (Sigma, Cat. no. A-7699) was used. After reacting at room temperature for 40 minutes, 5 μL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After completion of the reaction, 10 μL of the solution was instilled into GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed 3 times with 75 mM phosphoric acid solution for 5 minutes. Methanol drying was performed and scintillation was measured.
(2.3) JAK3
The final concentration of the substance contained in the 25 μL reaction solution is as shown in Table 3 below.
As γ- ³³ P-ATP, one produced from non-radiolabelled ATP (Sigma, Cat. no. A-7699) was used. After reacting at room temperature for 40 minutes, 5 μL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After completion of the reaction, 10 μL of the solution was instilled into GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed 3 times with 75 mM phosphoric acid solution for 5 minutes. Methanol drying was performed and scintillation was measured.
(2.4) TYK2
The final concentration of the substance contained in the 25 μL reaction solution is as shown in Table 4 below.
As γ- ³³ P-ATP, one produced from non-radiolabelled ATP (Sigma, Cat. no. A-7699) was used. After reacting at room temperature for 40 minutes, 5 μL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After completion of the reaction, 10 μL of the solution was instilled into GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed 3 times with 75 mM phosphoric acid solution for 5 minutes. Methanol drying was performed and scintillation was measured.
(2.5) Measurement of IC ₅₀ value In Examples 1 to 73, for some compounds (eg, Examples 5, 55 and 66), the concentrations were different and the inhibitory effect on JAK1, JAK2, JAK3 and TYK2 was observed. The IC ₅₀ value was measured by the method described above. IC ₅₀ values of test compounds were calculated from each% inhibition value of the compounds using the Cheng-Prusoff method (Biochem. Pharmacol. (1973) 22, 3099-3108).
(3) Test results Tables 5 and 6 show the results of measuring the degree to which the compounds synthesized in Examples 1 to 73 suppress the phosphorylation activity of JAK1, JAK2, JAK3 and TYK2 by the above-described method. . In Tables 5 and 6, the example numbers indicate the compounds synthesized in the examples, and the values in the JAK1, JAK2, JAK3 and TYK2 columns are the concentrations of the enzymes in the 1 μM concentration of the compounds synthesized in the examples. The degree of inhibition of phosphorylation activity is expressed as a percentage. In Tables 5 and 6, a negative value indicates that there is substantially no inhibitory effect.
The degree of inhibition indicates the percentage of decrease in phosphorylation activity measured in the experimental group relative to the phosphorylation activity obtained in the negative control group experiment not containing the compound.
% Inhibition = (scintillation measurement value of test substance untreated group−scintillation measurement value of test substance treatment group) / (scintillation measurement value of test substance treatment group) × 100
As a control group, Tofacitinib citrate (Hangzhou Tacon Co., Ltd.) 1 μM was used, and the ratios of inhibition against JAK1, JAK2, JAK3 and TYK2 were 99%, 98%, 99% and 100%, respectively.

Table 7 shows the IC ₅₀ for JAK1, JAK2, JAK3 and TYK2 activities of the compounds of Examples 5, 55, 66, 41 and 62.
As shown in Table 7, the compound of Example 5 having an R batch has a JAK1 inhibitory activity that is about 3.5 times higher than the compound of Example 55, which is its racemic mixture. Therefore, by separating a specific stereoisomer having a large inhibitory effect on JAK, for example, an optical isomer or a partial structural isomer, a disease associated with JAK can be efficiently treated.

2. Collagen-induced arthritis model (1) Obtain animal DBA / 1J mice (6 weeks old, male) via Japan SLC and observe the lighting for 12 hours, day / night cycle (07: 0 to 19:00) The temperature was maintained at 22 ° C. so that feed and drinking water could be freely used.
(2) Collagen induced arthritis (CIA) model generation method (CIA)
Store type 2 collagen (2 mg / mL volume, dissolved in 0.05 M acetic acid) at 4 ° C. until induction. On the first day of induction, before the implementation of primary immunization, a complete Freund immune enhancer of the same ratio and type 2 collagen are homogenized in a cooled tube using a homogenizer, and type 2 collagen and Freund immune enhancer And an emulsion mixed with was obtained. Primary emulsion was performed by injecting 0.1 mL of the emulsion into the tail of the mouse. 21 days after the primary immunization, an incomplete Freund's immune enhancer and type 2 collagen were mixed in the same manner for an enhanced immune reaction to produce an emulsion, and injected in the same manner as the primary immune reaction. This model generation method was carried out with some modifications to the method recorded in published books (David D Brand et al., Nature Protocols 2, 1269-1275 (2007)).
(3) Experimental design The therapeutic efficacy of the compound was confirmed in a collagen-derived mouse animal model. The mice were randomly separated into 8,9 animals per group. All mice were immunized as mentioned in (2) on day 1 and day 21 of the experiment and rheumatoid arthritis was induced. In order to confirm the therapeutic effect of the test drug, the negative control group and all drugs were advanced by oral administration once a day from the 22nd to 50th day of the experiment. Excipients used for administration were 0.45 v / v% carboxymethylcellulose (CMC) in distilled water (Sigma Aldrich, Cat. No. C5678, used in distilled water after manufacture at 0.5 v / v%) And an aqueous solution containing 10 v / v% ethanol. In the negative control group, the excipient alone was administered on a 1 mL basis per 100 g body weight, and in the positive control group, a solution containing 50 mg / 10 mL of tofacitinib citrate was added to the excipient. It was administered on a 1 mL basis per 100 g, so that the volume was 50 mg per kg body weight. Each test drug was prepared at a concentration of 15 mg / 10 mL and 50 mg / 10 mL, respectively, and was administered on a 1 mL basis per 100 g body weight, respectively, to 15 mg per kg body weight and 50 mg per kg body weight.
Tofacitinib oral citrate (Hangzhou Tacon Co., Ltd.) is a drug in the JAK inhibitor class and is approved for the treatment of rheumatoid arthritis (RA) in the United States and Russia, psoriasis (psoriasis), Clinical trials are underway for the treatment of inflammatory bowel disease (IBD) and other immunological diseases and the prevention of organ transplant rejection. Tofacitinib appears to show efficacy through inhibition of JAK3 and JAK1.
(4) Evaluation of arthritis model test The degree of arthritic disease was confirmed based on the degree of edema obtained by measuring the volume of the hind paw of the experimental animal. The volume was measured using a volume change flow meter (Plethysmometer, Havard apparatus, Cat. No. 760220, USA). At the time of measurement, the volume was measured from the knee of the hind paw to the tip of the mouse in a measuring cell. After measuring both feet, the value of the larger foot was used as a representative value. One day before the start of oral administration, the first measurement was performed, the volume was measured at intervals of a few days, and the value was recorded.
FIG. 1 is a drawing showing hind paw edema volume over time after primary immunization. In FIG. 1, the control group was administered with tofacitinib oral citrate from day 21 after the primary immunization, and the experimental group was synthesized in Example 5 from day 21 after the primary immunization (R) −. 3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile at 50 mg / It was administered in kg body weight. As can be seen from FIG. 1, on the 34th day after the primary immunization, the hind paw edema volume of the control group increased rapidly. On the other hand, in the case of the experimental group, the edema due to arthritis began to be significantly suppressed from the 31st day after the first immunization in which the edema of the control group began to increase. About 60% or more of the edema was continuously suppressed as compared with the control group, and about 64% of the edema was suppressed even on the 49th day when the measurement was completed. The result of FIG. 1 shows that the compound of Example 5 has the effect of suppressing the most typical edema among arthritic symptoms, and is effective as an arthritis therapeutic agent.

  A compound of formula 1 in a uniform phase, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof is used as an inhibitor of JAK.

  A pharmaceutical composition comprising a compound of Formula 1 according to another aspect, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, is used in the treatment of JAK-related diseases.

  According to the method for modulating the activity of JAK using the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer thereof according to another aspect, the activity of JAK is efficiently regulated. be able to.

  According to another aspect of the method of treating a disease in an individual, the compound of Formula 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, can treat the disease in the individual efficiently. it can.

Claims (14)

A compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer thereof,
Chemical formula 1
In Formula 1, R ¹ is C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, and R ² and R ³ are both — (C _2-6 alkyl) _-or — (C _2-6 alkenyl) -linked rings ,
R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ —, —S (═O) — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is H; halo; CN; NO ₂ ; N ₃ ; C _1-10 alkyl: C _2-10 alkenyl; C _2-10 alkynyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 C _5-20 aryl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl); C _3-7 cyclo Alkyl; heterocycloalkyl having 3 to 7 ring atoms, optionally substituted with —C (═O) 2 (C _1-6 alkyl); heteroaryl having 3 to 7 ring atoms; Heteroaryl- (C _1-10 alkyl) having 3 to 7 ring atoms;-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ;-( C _1-10 Alkyl) -O- (C _1-6 al) -(C _1-10 alkyl) -C (= O) NR ^a R ^b ; or-(C _1-10 alkyl) -NR ^a C (= O) R ^b or-(C _1-10 alkyl) —NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently of each other H or C _1-6 alkyl. The compound according to claim 1, wherein R ¹ is C _1-6 alkyl, and R ² and R ³ together _form- (C _2-6 alkyl)-. W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ — or —S (═O) ₂ —, R ⁵ is H or C _1-6 alkyl,
R ⁶ is selected from the group consisting of C _1-10 alkyl; C _1-6 haloalkyl; C _1-10 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ and —O— (C _1-10 alkyl). C _5-20 aryl; C _3-7 cycloalkyl; —C (═O) (C _1-6 alkyl), optionally substituted with one or more selected substituents; 3 Heterocycloalkyl having 3 to 7 ring atoms; heteroaryl having 3 to 7 ring atoms; -heteroaryl- (C _1-10 alkyl) having 3 to 7 ring atoms; C _1-10 alkyl) -CN _{;-( C 1-10 alkyl)} -N _{3 ;-( C 1-10} alkyl) -O- _{(C 1-6 alkyl) ;-( C 1-10} alkyl) -C (= O) NR ^a R ^b ; or-(C _{1- 10} alkyl) —NR ^a C (═O) R ^b or — (C _1-10 alkyl) —NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently of each other; The compound according to claim 1, which is H or C _1-6 alkyl. Having the general formula of Formula 2,
Chemical formula 2
In Formula 2, R ⁴ is —W ¹ —R ⁶ ,
W ¹ has no such atom, or —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ⁵ —, —C (= S) NR ⁵ — or —S (═O) ₂ —,
R ⁵ is H or C _1-6 alkyl;
R ⁶ is
When W ¹ does not have the atom, it is C _1-10 alkyl;
When W ¹ is —C (═O) —, C _1-10 alkyl; C _3-7 cycloalkyl;-(C _1-10 alkyl) -CN;-(C _1-10 alkyl) -N ₃ ; R ^a and R ^b are independently of each other —H or C _1-6 alkyl— (C _1-10 alkyl) —NR ^a C (═O) R ^b ; R ^e and R ^f are independently of each other; — (C _1-10 alkyl) —C (═O) N R ^e R ^f, which is H or C _1-6 alkyl; phenyl; substituted with one or more substituents selected from the group consisting of —CF ₃ and CN phenyl; -C (= _O) piperidinyl substituted with _{(C 1-6} alkyl); furanyl; pyridinyl; imidazolyl _{- (C 1-10 alkyl) ;-( C 1-10} alkyl) -O- (C _1-6 alkyl); or ^{R c} and ^{R d} are independently of each other, Or by _{C 1-6} alkyl _- a _{(C 1-10} alkyl) ^-NR c ^{R d,}
When W ¹ is —C (═S) —, it is — (C _1-10 alkyl) -CN;
When W ¹ is —C (═O) O—, it is — (C _1-10 alkyl);
When W ¹ is —C (═O) NR ⁵ , one or more selected from the group consisting of — (C _1-10 alkyl); C _3-7 cycloalkyl; phenyl; halo and C _1-10 alkyl Phenyl substituted with a substituent; biphenyl; or biphenyl substituted with one or more substituents selected from the group consisting of halo and C _1-10 alkyl;
When W ¹ is —C (═S) NR ^5, it is phenyl substituted with one or more —CF ₃ ;
When W ¹ is —S (═O) ₂ —, —C _1-10 alkyl; —CF ₃ ; piperidinyl; morpholinyl; R ^c and R ^d are each independently H or C _1-6 alkyl. -(C _1-10 alkyl) -NR ^c R ^d ; phenyl;-(C _1-10 alkyl), -O- (C _1-6 alkyl), -CF ₃ , NO ₂ , CN and halo independently. Phenyl substituted with one or more selected substituents; naphthalenyl; or — (C _1-10 alkyl), —O— (C _1-6 alkyl), — (C _1-6 haloalkyl), NO ₂ , CN And naphthalenyl substituted with one or more substituents independently selected from halo and halo. (R) -N- (5-butyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N-methyl-N- (5-pentyl-5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -2-Methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propane -1-one,
(R) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one,
(R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Nitrile,
(R) -3-Methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) butane -1-one,
(R) -N- (2- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2 -Oxoethyl) acetamide,
(R) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl)- 3-oxopropanamide,
(R) -cyclopropyl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methaneone,
(R) -1- (4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) piperidine- 1-yl) ethane-1-one,
(R) -furan-2-yl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methaneone,
(R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-3-yl) Methane-on,
(R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (phenyl) methaneone,
(R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-4-yl) Methane-on,
(R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile,
(R) -4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile,
(R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (2- (trifluoromethyl ) Phenyl) methanone,
(R)-(7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (3- (trifluoromethyl ) Phenyl) methanone,
(R) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo Propanenitrile, isobutyl (R) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate,
(R) -N-butyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide;
(R) -N-cyclohexyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide;
(R) -7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -N-phenyl-5-azaspiro [2.4] heptane-5-carboxamide;
(R) -N- (4-Fluorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide ,
(R) -N- (2,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide,
(R) -N- (3,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide,
(R) -N- (2,5-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide,
(R) -N- (2,3-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5 Carboxamide,
(R) -N- (3-Chloro-4-methylphenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide,
(R) -N-([1,1′-biphenyl] -2-yl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2 .4] heptane-5-carboxamide,
(R) -N- (3,5-bis (trifluoromethyl) phenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2. 4] heptane-5-carbothioamide,
(R) -N-methyl-N- (5-((trifluoromethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 An amine,
(R) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N- (5- (isopropylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N-methyl-N- (5- (propylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N- (5-((2-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N- (5-((3-Fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N- (5-((4-Fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -2-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile ,
(R) -3-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile ,
(R) -4-((7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile ,
(R) -N-methyl-N- (5-((2-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N-methyl-N- (5-((3-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N-methyl-N- (5-((4-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N-methyl-N- (5- (m-tolylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ,
(R) -N- (5-((4-methoxyphenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine- 4-amine,
(R) -N-methyl-N- (5-((4- (trifluoromethyl) phenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3- d] pyrimidine-4-amine,
(R) -N-methyl-N- (5- (naphthalen-2-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 An amine,
(R) -N-methyl-N- (5- (piperidin-1-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 An amine,
(R) -N-methyl-N- (5- (morpholinosulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine, 1 -(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one, 2-methoxy- 1- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane-1-one, 2-azido -1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane-1-one, 3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl Amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile, N- (2- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) ) Amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl) acetamide, N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidine-4) -Yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanamide, 3-amino-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidine) -4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one, 2- (1H-imidazol-1-yl) -1- (7- (methyl (7H- Pyrrolo [2,3-d] pyrimidine-4-i ) Amino) -5-azaspiro [2.4] heptan-5-yl) ethane-1-one, 3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxopropanenitrile, isobutyl 7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5 Azaspiro [2.4] heptane-5-carboxylate, N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3- d] pyrimidin-4-amine, N- (5-((2-aminoethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3- d] pyrimidine-4-amine,
(S) -1- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one ,
(S) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane -1-one,
(S) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropane Nitrile,
(S) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl)- 3-oxopropanamide,
(S) -4- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) benzonitrile,
(S) -3- (7- (Methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo Propanenitrile, isobutyl (S) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate,
(S) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(S) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine,
(R) -N- (5-ethyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; The compound according to claim 1, which is a pharmaceutically acceptable salt or solvate or stereoisomer. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is for treating a disease associated with JAK (Janus kinase). The pharmaceutical composition according to claim 7, wherein the disease is an autoimmune disease, immune dysfunction, viral disease or cancer. The autoimmune disease is skin disease, multiple sclerosis, rheumatoid arthritis, pediatric arthritis, type I diabetes, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, Crohn's disease or autoimmune thyroid disease, The immune dysfunction is allograft rejection, graft-versus-host disease, and the viral diseases are Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, chickenpox, shingles 9. The pharmaceutical composition according to claim 8, which is a viral (VZV) or human papillomavirus (HPV) disease, and wherein the cancer is prostate cancer, lymphoma, leukemia or multiple myeloma. 3. The activity of JAK comprising the step of contacting JAK (Janus kinase) with the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer, to regulate the activity of JAK. The method is performed in vitro or in non-human animals. A therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof , in the manufacture of a medicament used to treat an individual's disease , Use of . Use according to claim 11, characterized in that the disease is an autoimmune disease, immune dysfunction, viral disease or cancer. The autoimmune disease is skin disease, multiple sclerosis, rheumatoid arthritis, type I diabetes, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, Crohn's disease or autoimmune thyroid disease, Is allograft rejection, graft-versus-host disease, and the viral disease is Epstein-Barr virus (EBV), hepatitis B, hepatitis C, varicella or herpes zoster virus (VZV) disease Use according to claim 12, characterized in that the cancer is prostate cancer, lymphoma, leukemia or multiple myeloma. A method of producing a compound of formula 2 comprising reacting a compound of formula 9 or a salt thereof with a compound of R ⁴ -L ² to produce a compound of formula 2:
Chemical formula 9
Chemical formula 2
R ⁷ in Formula 9 represents a protecting group for H or an amino group, Formula 2 are as defined in claim 4, R ⁴ in the formula R ⁴ -L ^2, as defined in claim 4 And L ² is a leaving group.